Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL FORMULATIONS OF
AMYLOID INHIBITING COMPOUNDS
This application is a Continuation-in-part of U.S. Utility Application
10/871,549 and
a Continuation-in-part of published PCT application WO 2004/112762, filed June
21, 2004.
This application claims priority to U.S. provisional patent application no.
60/480,984, filed
June 23, 2003, identified by Attorney Docket No. NBI-152-l, and U.S.
provisional patent
application no. 60/512,116, filed October 17, 2003, identified by Attorney
Docket No. NBI-
152-2, and U.S. provisional patent application no. 60/640,108, filed December
29, 2004,
identified by Attorney Docket No. NBI-152CP-1, all entitled Pharmaceutical
Formulations of
Amyloid-Inhibiting Compounds.
Related Applications
This application is related to U.S. provisional application no. 60/436,379,
filed
December 24, 2002, identified by Attorney Docket No. NBI-154-1, entitled
Combination
Therapy for the Treatment of Alzheimer's Disease, U.S. provisional application
60/482,214,
filed June 23 2003, identified by Attorney Docket No. NBI-154-2, U.S. utility
patent
application no. 10/746,138, filed December 24; 2003, identified by Attorney
Docket No. NBI-
154, and International patent application no. PCT/CA2003/002011, identified by
NBI-154PC
entitled Therapeutic Formulations for the Treatment of Beta-Amydoid Related
Diseases. This
application is related to U.S. provisional patent application no. 60/482,058,
filed June 23,
2003, identified by Attorney Docket No. NBI-156-1, U.S. provisional patent
application no.
60/512,135, filed October 17, 2003, identified by Attorney Docket No. NBI-156-
2, both
entitled Synthetic Process for Preparing Compounds for Treating Amyloidosis,
and U.S.
application 10/871,543, filed June 18, 2004, identified by Attorney Docket No.
NBI-156,
entitled Improved Pharmaceutical Drug Candidates and Method for Preparation
Thereof.
This application is also related to US provisional patent application no.
60/480,918, filed June
23, 2003, identified by Attorney Docket No. NBI-149-1, U.S. provisional
application
60/512,017, filed October 17, 2003, identified by Attorney Docket No. NBI-149-
2, and US
patent application no. 1018? 1,613, filed Tune 18, 2004, identified by
Attorney Docket No.
NBI-149 entitled Methods for Treating Protein Aggregation Disorders. This
application is
also related to U.S. provisional patent application no. 60/480,906, filed June
23, 2003,
identified by Attorney Docket No. NBI-162-1, U.S. provisional patent
application no.
60/512,047, filed October 17, 2003, identified by Attorney Docket No. NBI-162-
2, U.S.
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CA 02504471 2005-04-12
application 10/871,514, filed June 18, 2004, identified by Attorney Docket No.
NBI-162A
and U.S. application 10/871,365, filed June 18, 2004, identified by Attorney
Docket No.
NCI-162B (formerly NBI-162B), all entitled Methods and Compositions for
Treating
Amyloid-Related Diseases; and U.S.'provisional patent application no.
60/480,928, also filed
23 June 2003, identified by Attorney Docket No. NBI-163-1, U.S. provisional
patent
application no. 60/512,018, filed October 17, 2003, identified by Attorney
Docket No. NBI-
163-2 and U.S. application 10/871,512, filed June 18, 2004, identified
by.Attorney Docket
No. NBI-163, all entitled Methods and Compositions for the Treatment of
Amyloid- and
Epileptogenesis-Associated Diseases; This application is also related to
Method for Treating
Amyloidosis, U.S. patent application no. 08/463,548, now U.S. Pat. No.
5,972,328, identified
by Attorney Docket No. NCI-003CP4. This application is also related to
Pharmaceutical
Formulations of Amyloid Inhibiting Compounds, U.S. provisional patent
application no.
60/640,108, filed December 29, 2004, identified by Attorney Docket No. NBI-
152CP-1.
The entire contents of each of the foregoing patent applications and patents
are
expressly incorporated by reference in their entirety including, without
limitation, the
specification, claims, and abstract, as well as any figures, tables, or
drawings thereof.
Background of the Invention
Amyloidosis refers to a pathological condition characterized by the presence
of
amyloid fibrils. Amyloid is a generic term refernng to a group of diverse but
specific protein
deposits (intracellular or extracellular) which are seen in a number of
different diseases.
Though diverse in their occurrence, all amyloid deposits have common
morphologic
properties, stain with specific dyes (e.g., Congo red), and have a
characteristic red-green
birefringent appearance in polarized light after staining. They also share
common
ultrastructural features and common X-ray diffraction and infrared spectra.
Amyloid-related diseases can either be restricted to one organ or spread to
several
organs. The first instance is referred to as "localized amyloidosis" while the
second is
referred to as "systemic amyloidosis."
Some amyloid diseases can be idiopathic, but most of these diseases appear as
a
complication of a previously existing disorder. For example, primary
amyloidosis (AL
amyloid) can appear without any other pathology or can follow plasma cell
dyscrasia or
multiple myeloma.
Secondary amyloidosis is usually seen associated with chronic infection (such
as
tuberculosis) or chronic inflammation (such as rheumatoid arthritis). A
familial form of
secondary amyloidosis is also seen in other types of familial amyloidosis,
e.g., Familial
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Mediterranean Fever ~. This familial type of amyloidosis is genetically
inherited and is
found in specific population groups. In both primary and secondary
amyloidosis, deposits are
found in several organs and are thus considered systemic amyloid diseases.
"Localized amyloidoses" are those that tend to involve a single organ system.
Different amyloids are also characterized by the type of protein present in
the deposit. For
example, neurodegenerative diseases such as scrapie, bovine spongiform
encephalitis,
Creutzfeldt-Jakob disease, and the like are characterized by the appearance
and accumulation
of a protease-resistant form of a prion protein (referred to as AScr or PrP-
27) in the central
nervous system. Similarly, Alzheimer's disease, another neurodegenerative
disorder, is
characterized by neuritic plaques and neurofibrillary tangles. In this case,
the amyloid
plaques found in the parenchyma and the blood vessel are formed by the
deposition of
fibrillar A(3 amyloid protein. Other diseases such as adult-onset diabetes
(type II diabetes) are
characterized by the localized accumulation of amyloid fibrils in the
pancreas.
Once these amyloids have formed, there is no known, widely accepted therapy or
treatment which significantly dissolves amyloid deposits in situ, prevents
further amyloid
deposition or prevents the initiation of amyloid deposition.
Each amyloidogenic protein has the ability to undergo a conformational change
and to
organize into ~i-sheets and form insoluble fibrils which may be deposited
extracellularly or
intracellularly. Each amyloidogenic protein, although different in amino acid
sequence, has
the same property of forming fibrils and binding to other elements such as
proteoglycan,
amyloid P and complement component. Moreover, each amyloidogenic protein has
amino
acid sequences which, although different, show similarities such as regions
with the ability to
bind to the glycosaminoglycan (GAG) portion of proteoglycan (referred to as
the GAG
binding site) as well as other regions which promote ~-sheet formation.
Proteoglycans are
macromolecules of various sizes and structures that are distributed almost
everywhere in the
body. They can be found in the intracellular compartment, on the surface of
cells, and as part
of the extracellular matrix. The basic structure of all proteoglycans is
comprised of a core
protein and at least one, but frequently more, polysaccharide chains (GAGs)
attached to the
core protein. Many different GAGS have been discovered including chondroitin
sulfate,
dermatan sulfate, keratan sulfate, heparin, and hyaluronan.
In specific cases, amyloid fibrils, once deposited, can become toxic to the
surrounding
cells. For example, the A(3 fibrils organized as senile plaques have been
shown to be
associated with dead neuronal cells, dystrophic neurites, astrocytosis, and
microgliosis in
patients with Alzheimer's disease. When tested in vitro, oligomeric (soluble)
as well as
fibrillar A(3 peptide was shown to be capable of triggering an activation
process of microglia
(brain macrophages), which would explain the presence of microgliosis and
brain
inflammation found in the brain of patients with Alzheimer's disease. Both
oligomeric and
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fibrillar A(3 peptide can also induce neuronal cell death in vitro. See, e.g.,
MP Lambert, et al.,
Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998).
In another type of amyloidosis seen in patients with type II diabetes, the
amyloidogenic protein IAPP, when organized in oligomeric forms or in fibrils,
has been
shown to induce (3-islet cell toxicity in vitro. Hence, appearance of IAPP
fibrils in the
pancreas of type II diabetic patients contributes to the loss of the (3 islet
cells (Langerhans)
and organ dysfunction which can lead to insulinemia.
Another type of amyloidosis is related to (32 microglobulin and is found in
long-term
hemodialysis patients. Patients undergoing long term hemodialysis will develop
(32-
microglobulin fibrils in the carpal tunnel and in the collagen rich tissues in
several joints.
This causes severe pain, joint stiffness and swelling.
Amyloidosis is also characteristic of Alzheimer's disease. Alzheimer's disease
is a
devastating disease of the brain that results in progressive memory loss
leading to dementia,
physical disability, and death over a relatively long period of time. With the
aging populations
in developed countries, the number of Alzheimer's patients is reaching
epidemic proportions.
People suffering from Alzheimer's disease develop a progressive dementia in
adulthood, accompanied by three main structural changes in the brain: diffuse
loss of neurons
in multiple parts of the brain; accumulation of intracellular protein deposits
termed
neurofibrillary tangles; and accumulation of extracellular protein deposits
termed amyloid or
senile plaques, surrounded by misshapen nerve terminals (dystrophic neurites)
and activated
microglia (microgliosis and astrocytosis)~ A-main constituent of these amyloid-
plaques is the
amyloid-(3 peptide (A~i), a 39-43 amino-acid protein that is produced through
cleavage of the
~-amyloid precursor protein (APP). Extensive research has been conducted on
the relevance
of A~3 deposits in Alzheimer's disease, see, e.g., Selkoe, Trends in Cell
Biology 8, 447-453
(1998). A(3 naturally arises from the metabolic processing of the amyloid
precursor protein
("APP") in the endoplasmic reticulum ("ER"), the Golgi apparatus, or the
endosomal-
lysosomal pathway, and most is normally secreted as a 40 ("A(31-40") or 42
("A(31-42")
amino acid peptide (Selkoe, Annu. Rev. Cell Biol. 10, 373-403 (1994)). A role
for A(3 as a
primary cause for Alzheimer's disease is supported by the presence of
extracellular A~3
deposits in senile plaques of Alzheimer's disease, the increased production of
A~i in cells
harboring mutant Alzheimer's disease associated genes, e.g., amyloid precursor
protein,
presenilin I and presenilin II; and the toxicity of extracellular soluble
(oligomeric) or
fibrillar A(3 to cells in culture. See, e.g., Gervais, Eur. Biopharm. Review,
40-42 (Autumn
2001); May, DDT 6, 459-62 (2001). Although symptomatic treatments exist for
Alzheimer's
disease, this disease cannot be prevented or cured at this time.
Alzheimer's disease is characterized by diffuse and neuritic plaques, cerebral
angiopathy, and neurofibrillary tangles. Plaque and blood vessel amyloid is
believed to be
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formed by the deposition of insoluble A(3 amyloid protein, which may be
described as diffuse
or fibrillary. Both soluble oligomeric A(3 and fibrillar A(3 are also believed
to be neurotoxic
and inflammatory.
Another type of amyloidosis is cerebral amyloid angiopathy (CAA). CAA is the
specific deposition of amyloid (3 fibrils in the walls of leptomingeal and
cortical arteries,
arterioles and veins. It is commonly associated with Alzheimer's disease,
Down's syndrome
and normal aging, as well as with a variety of familial conditions related to
stroke or dementia
(see Frangione et al., Amyloid: J. Protein Folding Disord. 8, Suppl. 1, 36-42
(2001)).
Presently available therapies for treatment of (3-amyloid diseases are almost
entirely
symptomatic, providing only temporary or partial clinical benefit. Although
some
pharmaceutical agents have been described that offer partial symptomatic
relief, no
comprehensive pharmacological therapy is currently available for the
prevention or treatment
of, for example, Alzheimer's disease.
Summary of the Invention
This invention provides methods, compositions, and formulations that are
useful in
the treatment of amyloidosis. The methods of the invention involve
administering to a
subject a therapeutic composition or formulation that inhibits amyloid
deposition.
Accordingly, the compositions and methods of the invention are useful for
inhibiting
amyloidosis disorders in which amyloid deposition occurs. The methods of the
invention
may be used therapeutically to treat amyloidosis or may be used
prophylactically in a subject
susceptible to amyloidosis.
In one aspect, the methods of the present invention are based, at least in
part, on
inhibiting an interaction between an amyloidogenic protein and a constituent
of a basement
membrane to inhibit amyloid deposition. In particular embodiments, the
constituent of the
basement membrane is a glycoprotein or proteoglycan, preferably agrin,
perlecan, or heparan
sulfate proteoglycan. A therapeutic compound used in the method of the
invention can
interfere with binding of a basement membrane constituent to a target binding
site on an
amyloidogenic protein, thereby inhibiting amyloid deposition. In other
embodiments, a
therapeutic compound used in the method of the invention can enhance clearance
of amyloid
~i from the brain, thereby inhibiting amyloid deposition. In other
embodiments, a therapeutic
compound used in the method of the invention can inhibit neurodegeneration or
cellular
toxicity induced by amyloid (e.g., by soluble or insoluble amyloid, e.g.,
fibrils, by amyloid
deposition and/or by amyloid-(3, as described herein).
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In another aspect, the invention relates to the use of alkylsulfonic acids in
the
treatment of amyloid-related diseases.
Accordingly, in one aspect, the invention is directed to a method for
inhibiting
amyloid deposition in a subject comprising administering to the subject an
effective amount
of a therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, such that amyloid deposition
is inhibited.
In another aspect, the invention pertains to a method of treating or
preventing an
amyloid-related disease, e.g., A(3-related disease, in a subject, comprising
administering to a
subject a therapeutic amount of a therapeutic formulation comprising a
therapeutic compound
formulated to significantly reduce or prevent gastrointestinal intolerance,
such that the
amyloid-related disease is treated or prevented.
In an additional aspect, the invention is a method for inhibiting amyloid
deposition in
a subject comprjsing administering to the subject an effective amount of a
therapeutic
formulation comprising a therapeutic compound formulated to significantly
reduce or prevent
gastrointestinal intolerance, such that the therapeutic compound inhibits an
interaction
between an amyloidogenic protein and a constituent of a basement membrane to
inhibit
amyloid deposition.
Another aspect of the invention involves a method for inhibiting amyloid
deposition
in a subject comprising administering to the subject an effective amount of a
therapeutic
formulation comprising a therapeutic compound formulated to significantly
reduce or prevent
gastrointestinal intolerance, such that the therapeutic compound inhibits
neurodegeneration or
cellular toxicity induced by amyloid (e.g., by soluble or insoluble amyloid,
e.g., fibrils, by
amyloid deposition and/or by amyloid-Vii, as described herein).
In another aspect, the invention is directed to a method for inhibiting
amyloid
deposition in a subject comprising administering to the subject an effective
amount of a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, such that the therapeutic
compound enhances
clearance of amyloid (3 from the brain.
In yet another aspect, the invention pertains to a method for inhibiting
amyloid
deposition in a subject comprising orally administering to the subject an
effective amount of a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance.
An additional aspect of the invention is a pharmaceutical composition for
inhibiting
amyloid deposition in a subject comprising a therapeutic formulation
comprising a
therapeutic compound formulated to significantly reduce or prevent
gastrointestinal
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intolerance, in an amount sufficient to inhibit amyloid deposition in a
subject, and a
pharmaceutically acceptable vehicle.
In another aspect, the invention is directed to a pharmaceutical composition
for
treating amyloidosis comprising a therapeutic formulation comprising a
therapeutic
compound formulated to significantly reduce or prevent gastrointestinal
intolerance, in an
amount sufficient to treat amyloidosis in a subject, and a pharmaceutically
acceptable
vehicle.
In another aspect, the present invention pertains to a pharmaceutical
composition for
treating or preventing an amyloid-related disease, e.g., A(3-related disease,
comprising a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, in an amount sufficient to
prevent or treat an
amyloid-related disease in a subject, and a pharmaceutically acceptable
vehicle.
In yet another aspect, the invention pertains to a method for reducing amyloid
deposits
in a subject having amyloid deposits, the method comprising administering to
the subject an
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance, such that
amyloid deposits are
reduced in the subject.
Another aspect of the invention is directed to a method for inhibiting the
binding of a
chemokine to a glycosaminoglycan in a subject comprising administering to the
subject a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, such that the binding of a
chemokine to a
glycosaminoglycan is inhibited.
Yet another aspect of the invention is directed to a method for modulating
interaction
between a bacterium and a glycosaminoglycan in a human comprising
administering to the
human an effective amount of a therapeutic formulation comprising a
therapeutic compound
formulated to significantly reduce or prevent gastrointestinal intolerance.
In an additional aspect, the invention pertains to a method for treating a
bacterial
infection in a human comprising administering to the human an effective amount
of a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance.
In another aspect, the invention is a method for modulating interaction
between a
virus and a glycosaminoglycan in a subject comprising administering to the
subject an
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance.
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Another aspect of the invention is a method for treating a viral infection in
a subject
comprising administering to the subject a therapeutic formulation comprising
an effective
amount of a therapeutic formulation comprising a therapeutic compound
formulated to
significantly reduce or prevent gastrointestinal intolerance.
Yet another aspect of the invention is directed to a method of preventing,
treating or
inhibiting cerebral amyloid angiopathy in a subject, comprising administering
an effective
amount of a therapeutic formulation comprising a therapeutic compound
formulated to
significantly reduce or prevent gastrointestinal intolerance.
In an additional aspect, the invention pertains to a method of preventing,
treating or
inhibiting cerebral amyloid angiopathy, comprising contacting a blood vessel
wall cell with a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, such that cerebral amyloid
angiopathy is
prevented, treated, or inhibited.
In another aspect, the invention pertains to a method of preventing, treating
or
inhibiting cerebral amyloid angiopathy, comprising contacting a blood vessel
wall cell with a
therapeutic compound of a therapeutic formulation, formulated to significantly
reduce or
prevent gastrointestinal intolerance, such that cerebral amyloid angiopathy is
prevented,
treated, or inhibited.
An additional aspect of the present invention is directed to a method of
preventing,
treating or inhibiting Alzheimer's disease in a subject, comprising
administering to the
subject an effective amount of a therapeutic formulation comprising a
therapeutic compound
formulated to significantly reduce or prevent gastrointestinal intolerance.
An additional aspect of the present invention is directed to a method of
preventing,
treating or inhibiting Alzheimer's disease in a subject, comprising
administering to the
subject an effective amount of a therapeutic formulation comprising a
therapeutic compound
formulated to significantly reduce or prevent gastrointestinal intolerance,
such that
Alzheimer's disease is prevented, treated, or inhibited.
In another aspect, the invention is directed to a packaged pharmaceutical
composition
for inhibiting amyloid deposition in a subject, comprising a container holding
a
therapeutically effective amount of a therapeutic formulation comprising a
therapeutic
compound formulated to significantly reduce or prevent gastrointestinal
intolerance; and
instructions for using the compound for inhibiting amyloid deposition in a
subject.
In yet another aspect, the invention pertains to a packaged pharmaceutical
composition for treating amyloidosis in a subject, comprising a container
holding a
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therapeutically effective amount of a therapeutic formulation comprising a
therapeutic
compound formulated to significantly reduce or prevent gastrointestinal
intolerance; and
instructions for using the compound for treating amyloidosis in a subject.
In yet another aspect, the invention pertains to a packaged pharmaceutical
composition for treating Alzheimer's disease in a subject, comprising a
container holding a
therapeutically effective amount of a therapeutic formulation comprising a
therapeutic
compound formulated to significantly reduce or prevent gastrointestinal
intolerance; and
instructions for using the compound for treating Alzheimer's disease in a
subject.
Another aspect of the invention is a packaged pharmaceutical composition for
treating
a viral infection, comprising a container holding a therapeutically effective
amount of a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance; and instructions for using the
compound for
treating the viral infection.
In an additional aspect, the invention is directed to a packaged
pharmaceutical
composition for treating a bacterial infection, comprising a container holding
a therapeutically
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance; and
instructions for using the
therapeutic compound for treating the bacterial infection.
In another aspect, the invention pertains to a packaged pharmaceutical
composition for
inhibiting the binding of a chemokine to a glycosaminoglycan, comprising a
container
holding a therapeutically effective amount of a therapeutic formulation
comprising a
therapeutic compound formulated to significantly reduce or prevent
gastrointestinal
intolerance; and instructions for using the therapeutic compound for
inhibiting the binding of
a chemokine to a glycosaminoglycan.
In yet another aspect, the invention pertains to method of making a
therapeutic
formulation comprising combining a therapeutically effective amount of a
therapeutic
compound and a pharmaceutically acceptable vehicle, wherein the therapeutic
formulation is
formulated to significantly reduce or prevent gastrointestinal intolerance.
An additional aspect of the invention is directed to a pharmaceutical
formulation
comprising greater than 5% by weight of 3-amino-1-propanesulfonic acid ("3-
APS").
In another aspect, the invention is a pharmaceutical formulation comprising a
therapeutic compound and greater than 1 % by weight of an additional agent.
In yet another aspect, the invention pertains to a method for inhibiting
amyloid
deposition in a subject comprising administering to the subject an effective
amount of a
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therapeutic formulation comprising a therapeutic compound formulated with an
enteric-
coating, such that amyloid deposition is inhibited.
Another aspect of the invention is directed to a method for inhibiting amyloid
deposition in a subject comprising administering to the subject an effective
amount of a
therapeutic formulation comprising a therapeutic compound formulated with an
agent that
modifies the release of the therapeutic compound, such that amyloid deposition
is inhibited.
Additionally, a further aspect of the invention is a pharmaceutical
composition for
inhibiting amyloid deposition in a subject comprising a therapeutic compound
formulated
with an enteric-coating, such that amyloid deposition is inhibited.
In another aspect, the present invention pertains to a pharmaceutical
composition for
inhibiting amyloid deposition in a subject comprising a therapeutic compound
formulated
with an agent that modifies the release of the therapeutic compound, such that
amyloid
deposition is inhibited.
In yet another aspect, the invention pertains to a method of formulating a
gastrointestinal intolerance enhanced pharmaceutical composition comprising:
combining a
pre-selected therapeutic compound with a pharmaceutically acceptable carrier,
wherein the
therapeutic compound is pre-selected for its ability to significantly reduce
or prevent
gastrointestinal intolerance, forming a gastrointestinal intolerance enhanced
pharmaceutical
composition.
In an additional aspect, the invention is directed to a method for preventing
or treating
amyloid-related disease in a subject comprising administering to the subject
an effective
amount of a therapeutic formulation comprising a therapeutic compound
formulated with an
enteric-coating, such that amyloid-related disease is prevented or treated.
Another aspect of the invention is a method for preventing or treating amyloid-
related
disease in a subject comprising administering to the subject an effective
amount of a
therapeutic formulation comprising a therapeutic compound formulated with an
agent that
modifies the release of the therapeutic compound, such that amyloid-related
disease is
prevented or treated.
In another aspect, the invention is directed to a pharmaceutical composition
for
preventing or treating amyloid-related disease in a subject comprising a
therapeutic
compound formulated with an enteric-coating.
In yet another aspect, the invention pertains to a pharmaceutical composition
for
preventing or treating amyloid-related disease in a subject comprising a
therapeutic
compound formulated with an agent that modifies the release of the therapeutic
compound.
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Another aspect of the invention is a method for inhibiting amyloid deposition
in a
subject comprising administering to the subject an effective amount of a
therapeutic
formulation comprising a therapeutic compound formulated to significantly
reduce or prevent
gastrointestinal intolerance, wherein the therapeutic formulation is
formulated as described in
Example 6, such that amyloid deposition is inhibited.
Yet another aspect of the invention pertains to a method of treating or
preventing an
amyloid-related disease in a subject comprising administering to a subject a
therapeutic
amount of a therapeutic formulation comprising a therapeutic compound
formulated to
significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6, such that the amyloid-
related disease is
treated or prevented.
In another aspect, the invention is a method for inhibiting amyloid deposition
in a
subject comprising administering to the subject an effective amount of a
therapeutic
formulation comprising a therapeutic compound formulated to significantly
reduce or prevent
gastrointestinal intolerance, wherein the therapeutic formulation is
formulated as described in
Example 6, such that the therapeutic compound inhibits an interaction between
an
amyloidogenic protein and a constituent of a basement membrane to inhibit
amyloid
deposition.
In yet another aspect, the invention is directed to a method for inhibiting
amyloid
deposition in a subject comprising administering to the subject an effective
amount of a
therapeutic formulation comprising-a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, wherein the therapeutic
formulation is
formulated as described in Example 6, such that the therapeutic compound
inhibits
neurodegeneration or cellular toxicity induced by amyloid.
An additional aspect of the invention pertains to a method for inhibiting
amyloid
deposition in a subject comprising administering to the subject an effective
amount of a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, wherein the therapeutic
formulation is
formulated as described in Example 6, such that the therapeutic compound
enhances
clearance of amyloid ~ from the brain.
In an additional aspect, the invention is a method for inhibiting amyloid
deposition in
a subject comprising orally administering to the subject an effective amount
of a therapeutic
formulation comprising a therapeutic compound formulated to significantly
reduce or prevent
gastrointestinal intolerance, wherein the therapeutic formulation is
formulated as described in
Example 6, such that amyloid deposition is inhibited.
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Another aspect of the invention is directed to a pharmaceutical composition
for
inhibiting amyloid deposition in a subject comprising a therapeutic
formulation comprising a
therapeutic compound formulated to significantly reduce or prevent
gastrointestinal
intolerance, in an amount sufficient to inhibit amyloid deposition in a
subject, and a
pharmaceutically acceptable vehicle, wherein the therapeutic formulation is
formulated as
described in Example 6.
In yet another aspect, the invention is a pharmaceutical composition for
treating
amyloidosis comprising a therapeutic formulation comprising a therapeutic
compound
formulated to significantly reduce or prevent gastrointestinal intolerance, in
an amount
sufficient to treat amyloidosis in a subject, and a pharmaceutically
acceptable vehicle,
wherein the therapeutic formulation is formulated as described in Example 6.
An additional aspect of the invention is directed to a pharmaceutical
composition for
treating or preventing an amyloid-related disease comprising a therapeutic
formulation
comprising a therapeutic compound formulated to significantly reduce or
prevent
gastrointestinal intolerance, in an amount sufficient to prevent or treat an
amyloid-related
disease in a subject, and a pharmaceutically acceptable vehicle, wherein the
therapeutic
formulation is formulated as described in Example 6.
In an additional aspect, the invention pertains to a method for reducing
amyloid
deposits in a subject having amyloid deposits, the method comprising
administering to the
subject an effective amount-of a therapeutic formulation comprising,a
therapeutic compound
formulated to significantly reduce or prevent gastrointestinal intolerance,
wherein the
therapeutic formulation is formulated as described in Example 6, such that
amyloid deposits
are reduced in the subject.
In another aspect, the invention is directed to a method for inhibiting the
binding of a
chemokine to a glycosaminoglycan in a subject comprising administering to the
subject a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, wherein the therapeutic
formulation is
formulated as described in Example 6, such that the binding of a chemokine to
a
glycosaminoglycan is inhibited.
Another aspect of the invention pertains to a method for modulating
interaction
between a bacterium and a glycosaminoglycan in a human comprising
administering to the
human an effective amount of a therapeutic formulation comprising a
therapeutic compound
formulated to significantly reduce or prevent gastrointestinal intolerance,
wherein the
therapeutic formulation is formulated as described in Example 6.
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CA 02504471 2005-04-12
An additional aspect of the invention pertains to a method for treating a
bacterial
infection in a human comprising administering to the human an effective amount
of a
therapeutic formulation comprising a therapeutic compound formulated to
significantly
reduce or prevent gastrointestinal intolerance, wherein the therapeutic
formulation is
formulated as described in Example 6.
In another aspect, the invention is directed to a method for modulating
interaction
between a virus and a glycosaminoglycan in a subject comprising administering
to the subject
an effective amount of a therapeutic formulation comprising a therapeutic
compound
formulated to significantly reduce or prevent gastrointestinal intolerance,
wherein the
therapeutic formulation is formulated as described in Example 6.
In yet another aspect, the invention is a method for treating a viral
infection in a
subject comprising administering to the subject a therapeutic formulation
comprising an
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6.
Another aspect of the invention pertains to a method of preventing, treating
or
inhibiting cerebral amyloid angiopathy in a subject, comprising administering
an effective
amount of a therapeutic formulation comprising a therapeutic compound
formulated to
significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6.
In an additional aspect, the invention is directed to a method of preventing,
treating or
inhibiting cerebral amyloid angiopathy, comprising contacting a blood vessel
wall cell with a
therapeutic formulation therapeutic formulation comprising a therapeutic
compound
formulated to significantly reduce or prevent gastrointestinal intolerance,
wherein the
therapeutic formulation is formulated as described in Example 6, such that
cerebral amyloid
angiopathy is prevented, treated, or inhibited.
An additional aspect of the invention pertains to a method of preventing,
treating or
inhibiting cerebral amyloid angiopathy, comprising contacting a blood vessel
wall cell with a
therapeutic compound of a therapeutic formulation therapeutic formulation,
formulated to
significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6, such that cerebral
amyloid angiopathy is
prevented, treated, or inhibited.
In another aspect, the invention is directed to a method of preventing or
treating
Alzheimer's disease in a subject, comprising administering to the subject an
effective amount
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CA 02504471 2005-04-12
of a therapeutic formulation comprising a therapeutic compound formulated to
significantly I
reduce or prevent gastrointestinal intolerance, wherein the therapeutic
formulation is
formulated as described in Example 6.
In yet another aspect, the invention is a packaged pharmaceutical composition
for
inhibiting amyloid deposition in a subject, comprising a container holding a
therapeutically
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6; and instructions for
using the
compound for inhibiting amyloid deposition in a subject.
Another aspect of the invention pertains to a packaged pharmaceutical
composition
for treating amyloidosis in a subject, comprising a container holding a
therapeutically
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6; and instructions for
using the
compound for treating amyloidosis in a subject.
An additional aspect of the invention pertains to a packaged pharmaceutical
composition for treating a viral infection, comprising a container holding a
therapeutically
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6; and instructions for
using the
compound for treating the viral infection.
In another aspect, the invention is directed to a packaged pharmaceutical
composition
for treating a bacterial infection, comprising a container holding a
therapeutically effective
amount of a therapeutic formulation comprising a therapeutic compound
formulated to
significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6; and instructions for
using the
therapeutic compound for treating the bacterial infection.
In yet another aspect, the invention is a packaged pharmaceutical composition
for
inhibiting the binding of a chemokine to a glycosaminoglycan, comprising a
container
holding a therapeutically effective amount of a therapeutic formulation
comprising a
therapeutic compound formulated to significantly reduce or prevent
gastrointestinal
intolerance, wherein the therapeutic formulation is formulated as described in
Example 6; and
instructions for using the therapeutic compound for inhibiting the binding of
a chemokine to a
glycosaminoglycan.
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CA 02504471 2005-04-12
An additional aspect of the invention pertains to a method of making a
therapeutic
formulation comprising combining a therapeutically effective amount of a
therapeutic
compound and a pharmaceutically acceptable vehicle, wherein the therapeutic
formularion is
formulated to significantly reduce or prevent gastrointestinal intolerance,
and wherein the
therapeutic formulation is formulated as described in Example 6.
In another aspect, the invention is directed to a method for inhibiting
amyloid
deposition in a subject comprising administering to the subject an effective
amount of a
therapeutic formulation comprising a therapeutic compound formulated with an
enteric-
coating, wherein the therapeutic formulation is formulated as described in
Example 6, such
that amyloid deposition is inhibited.
In yet another aspect, the invention is a method for inhibiting amyloid
deposition in a
subject comprising administering to the subject an effective amount of a
therapeutic
formulation comprising a therapeutic compound formulated with an agent that
modifies the
release of the therapeutic compound, wherein the therapeutic formulation is
formulated as
described in Example 6, such that amyloid deposition is inhibited.
Another aspect of the invention pertains to a pharmaceutical composition for
inhibiting amyloid deposition in a subject comprising a therapeutic compound
formulated
with an enteric-coating, wherein the therapeutic formulation is formulated as
described in
Example 6.
In an additional aspect, the invention is directed to a pharmaceutical
composition for
inhibiting amyloid deposition in a subject comprising a therapeutic compound
formulated
with an agent that modifies the release of the therapeutic compound, wherein
the therapeutic
formulation is formulated as described in Example 6.
An additional aspect of the invention pertains to a method of formulating a
gastrointestinal intolerance enhanced pharmaceutical composition comprising:
combining a
pre-selected therapeutic compound with a pharmaceutically acceptable carrier,
wherein the
therapeutic compound is pre-selected for its ability to significantly reduce
or prevent
gastrointestinal intolerance, forming a gastrointestinal intolerance enhanced
pharmaceutical
composition as described in Example 6.
In another aspect, the invention is directed to a method for preventing or
treating
amyloid-related disease in a subject comprising administering to the subject
an effective
amount of a therapeutic formulation comprising a therapeutic compound
formulated with an
enteric-coating, wherein the therapeutic formulation is formulated as
described in Example 6,
such that amyloid-related disease is prevented or treated.
In yet another aspect, the invention is a method for preventing or treating
amyloid-
related disease in a subject comprising administering to the subject an
effective amount of a
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CA 02504471 2005-04-12
therapeutic formulation comprising a therapeutic compound formulated with an
agent that
modifies the release of the therapeutic compound, wherein the therapeutic
formulation is
formulated as described in Example 6, such that amyloid-related disease is
prevented or
treated.
Another aspect of the invention pertains to a pharmaceutical composition for
preventing or treating amyloid-related disease in a subject comprising a
therapeutic
compound formulated with an enteric-coating, wherein the therapeutic
formulation is
formulated as described in Example 6.
An additional aspect of the invention pertains to a pharmaceutical composition
for
preventing or treating amyloid-related disease in a subject comprising a
therapeutic
compound formulated with an agent that modifies the release of the therapeutic
compound,
wherein the therapeutic formulation is formulated as described in Example 6.
In another aspect, the invention is directed to a method of preventing,
treating or
inhibiting Alzheimer's disease in a subject, comprising administering to the
subject an
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6, such that Alzheimer's
disease is
prevented, treated, or inhibited.
In yet another aspect, the invention is a packaged pharmaceutical composition
for
treating Alzheimer's disease in a subject, comprising a container holding a
therapeutically
effective amount of a therapeutic formulation comprising a therapeutic
compound formulated
to significantly reduce or prevent gastrointestinal intolerance, wherein the
therapeutic
formulation is formulated as described in Example 6; and instructions for
using the
compound for treating Alzheimer's disease in a subject.
Another aspect of the invention is a formulation, preferably oral, comprising
3-amino-
1-propanesulfonic acid (i.e., 3-APS) or a pharmaceutically acceptable salt
thereof in an
effective amount to treat amyloidosis, inhibit or prevent amyloid deposition
and/or treat or
prevent an amyloid-related disease and a pharmaceutically acceptable vehicle,
wherein the
formulation has a mean plasma concentration pharmacokinetic (PK) profile such
that, when
the formulation is administered in a dose of 50 mg of the active agent, e.g.,
to patients
suffering from mild to moderate Alzheimer's disease, e.g., in a fasted state,
said PK profile
has at least one of the following parameters: a mean AUCo_t of about 1321
ng~h/mL, a mean
AUC~ of about 1396 ng~h/mL, a mean Cmax of about 310 ng/mL, and a median Tmax
of
about 6 hours (each parameter being within ~ 50%, more preferably ~ 40% and
particularly
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CA 02504471 2005-04-12
preferably ~ 20% of said respective value, (see Example 10 below)), or, when
the formulation
is administered in another dose amount, a mean AUCo_t, AUC~ and Cmax linearly
related to
that for the 50 mg dose are achieved. In a modification of this aspect, the
mean AUCo_~ is in
the range from 126 to 4259, preferably 500 to 2500, ng~h/mL, the mean AUC~ is
in the range
from 157 to 4311, preferably 500 to 2500, ng~h/mL, the mean Cmax is in the
range from 27
to 776, preferably 100 to 500, ng/mL, and the median Tmax is in the range from
2 to 9 hours,
preferably 4 to 8 hours, (optionally, the respective minimum and maximum
values of the
ranges being ~ 50%, more preferably ~ 40% and particularly preferably ~ 20% ).
Another aspect of the invention is a formulation, preferably oral, comprising
3-amino-
1-propanesulfonic acid (i.e., 3-APS) or a pharmaceutically acceptable salt
thereof in an
effective amount to treat amyloidosis, inhibit or prevent amyloid deposition
and/or treat or
prevent an amyloid-related disease and a pharmaceutically acceptable vehicle,
wherein the
formulation has a mean plasma concentration (pharmacokinetic (PK)) profile
such that, when
the formulation is administered in a dose of 100 mg of the active agent, e.g.,
to patients
suffering from mild to moderate Alzheimer's disease, e.g., in a fasted state,
said PK profile
has at least one of the following parameters: a mean AUCo_~ of about 2467
ng~h/mL, a mean
AUC~ of about 2569 ng~h/mL, a mean Cmax of about 618 ng/mL, and a median Tmax
of
about 4.7 hours, each parameter being within t 50%, more preferably t 40% and
particularly
preferably ~ 20% of said respective value, (see Example 10 below), or, when
the formulation
is administered in another dose amount, a mean AUC0.t, AUC~ and Cmax linearly
related to
that for the 100 mg dose are achieved. In a modification of this aspect, the
mean AUCo_, is in
the range from 829 to 5123, preferably 1500 to 3500 ng~h/mL, the mean AUC~ is
in the range
from 861 to 5385, preferably 1500 to 3500 ng~h/mL, the mean Cmax is in the
range from 220
to 1666, preferably 300 to 1000, ng/mL, and the median Tmax is in the range
from 2 to 8
hours, preferably 4 to 7 hours (optionally, the respective minimum and maximum
values of
the ranges being ~ 50%, more preferably ~ 40% and particularly preferably ~
20% ).
Another aspect of the invention is a formulation, preferably oral, comprising
3-amino-
1-propanesulfonic acid (i.e., 3-APS) or a pharmaceutically acceptable salt
thereof in an
effective amount to treat amyloidosis, inhibit or prevent amyloid deposition
and/or treat or
prevent an amyloid-related disease and a pharmaceutically acceptable vehicle,
wherein the
formulation has a mean plasma concentration pharmacokinetic (PK) profile such
that, when
the formulation is administered in a dose of 150 mg of the active agent, e.g.,
to patients
suffering from mild to moderate Alzheimer's disease, e.g., in a fasted state,
said PK profile
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has at least one of the following parameters: a mean AUCo_~ of about 2792
ng~h/mL, a mean
AUC~ of about 3418 ng~h/mL, a mean Cmax of about 624 ng/mL, a median Tmax of
about 6
hours, each parameter being within t 50%, more preferably t 40% and
particularly preferably
t 20% of said respective value, (see Example 10 below), or, when the
formulation is
administered in another dose amount, a mean AUCa~, AUC~ and Cmax linearly
related to
that for the 150 mg dose are achieved. In a modification of this aspect, the
mean AUCo_~ is in
the range from 75 to 9042, preferably 1000 to 5000 ng~h/mL, the mean AUC~ is
in the range
from 670 to 9627, preferably 1000 to 5000, ng~h/mL, the mean Cmax is in the
range from 14
to 1875, preferably 300 to 1000, ng/mL, and the median Tmax is in the range
from 2 to 12
hours, preferably 4 to 9 hours (optionally, the respectlve minimum and maximum
values of
the ranges being ~ 50%, more preferably ~ 40% and particularly preferably ~
20% ).
Another aspect of the invention is a formulation, preferably oral, comprising
3-amino-
1-propanesulfonic acid (i.e., 3-APS) or a pharmaceutically acceptable salt
thereof in an
effective amount to treat amyloidosis, inhibit or prevent amyloid deposition
and/or treat or
prevent an amyloid-related disease and a pharmaceutically acceptable vehicle,
wherein the
formulation has pharmacoltinetic parameters (within ~ 50%, more preferably t
40% and
particularly preferably t 20%) of those shown in each of Examples 7 to 10
below, in the types
of patients as shown (e.g., young and healthy, elderly and healthy, fasted or
fed, etc.).
Further aspects of the invention include formulations which combine two or
more of
the pharmacokinetic parameters, or sets of pharmacokinetic parameters (e.g.,
AUCc.,, AUC~,
Cmax and/or Tmax), described above. For example, such aspects include
formulations which
provide one or more of the pharmacokinetic parameters, or sets thereof, as
shown herein
when administered to young healthy patients and one or more of the
pharmacokinetic
parameters, or sets thereof, as shown herein when administered to elderly
healthy patients
and/or elderly patients with Alzheimer's Disease (AD) or exhibiting one or
more of the
indicators for AD as discussed herein. It has been discovered that there is an
effect of age on
the pharmacoltinetic parameters observed for 3-APS. Elderly patients exhibited
a higher
systemic exposure to the drug than younger patients when subjected to the same
dose. For
example, at a 200 mg dose, the AUCa~ and Cm~ were approximately 70% greater in
elderly
subjects compared to those for young subjects. See, e.g., Tables 9 and 10
below.
A further aspect includes formulations as described above wherein the
formulation
includes an enteric coating and/or a pharmaceutically acceptable vehicle,
different from the
enteric coating, which modifies immediate release of the active agent. A
further aspect
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includes formulations as described above wherein the formulation is effective
for osmotic
release, pulsatile release, sustained release, controlled release, delayed
release, extended
release, or other modified release of the active agent.
In another aspect, the active agent is provided in an oral therapeutic
formulation such
that little or no dissolution of the active agent occurs in the acidic
environment of the stomach
but dissolution does occur in the more neutral or alkaline environments of the
GI tract.
Although there is no limitation, the active agent may, for example, be
provided in a
formulation which has 20% or less dissolution in the stomach, more preferably
15% or less,
particularly 10% or less or 5% or less. In vitro dissolution tests, according
to known
standards, may be used to give a reasonable indication of what can be expected
in vivo. For
example, one test for in vitro dissolution of pH dependent enteric materials
is USP28-NF23
<711> (paddle speed 75 rpm) and it requires no more than 10% release in O.1N
HCl for 2
hours. The buffer is then switched to a more alkaline buffer based on the type
of enteric
coating, for example, a pH of 6-8, particularly 6.5 to 7.0, such as 6.8. After
the pH change,
the dissolution of the active agent increases, for example, at least 75% is
dissolved within 60
minutes of buffer change. Enteric formulations which are pH independent can
also be used,
as is known in the art. These provide for release of the drug after a certain
time, independent
of the pH. Standards for assessing dissolution of such formulations are also
known.
Although these tests are conducted in vitro and give a reasonable indication
of what can be
expected in vivo, it is well understood in the art that in vivo dissolution in
the stomach and
G.I. tract are affected by many factors. One of the main factors is whether
the stomach is in a
fed or fasted state. Gastric emptying times in the fasted state range from,
for example, 30
minutes to 2 hours, while in the fed state gastric emptying is generally
significantly slower,
e.g., as slow as 7 hours. Thus, for pH independent enteric formulations, it
may be useful to
provide formulations which delay significant dissolution, e.g., no more than
20%, 15%, 10%
or 5%, for from 30 minutes up to 3 hours, for example, 1-2 hours, or 2 hours,
after
administration.
Further aspects of the invention include methods for administering the above
formulations. Included are:
- methods for lessening gastrointestinal side effects in a human patient which
occur
from orally administering an active agent which is 3-amino-1-propanesulfonic
acid or a
pharmaceutically acceptable salt thereof, comprising administering said agent
in a
formulation effective to lessen the increase in pH of the stomach when
administered
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compared to that which occurs when said agent is administered in an immediate
release
dosage form;
- methods of lessening gastrointestinal side effects in a human patient which
occur
from orally administering an active agent which is 3-amino-1-propanesulfonic
acid or a
pharmaceutically acceptable salt thereof, comprising administering said agent
in a
formulation, as disclosed herein, which is effective to treat amyloidosis,
inhibit or prevent
amyloid deposition and/or treat or prevent an amyloid-related disease with
lesser side effects
in comparison to those which occur when said active agent is administered in
an immediate
release dosage form, the immediate release dosage formulation compared being,
for example,
that described in Table 2 below;
- methods of orally administering an active agent which is 3-amino-1-
propanesulfonic
acid or a pharmaceutically acceptable salt thereof in a formulation which is
effective to treat
amyloidosis, inhibit or prevent amyloid deposition and/or treat or prevent an
amyloid-related
disease with a low occurrence of side effects, particularly a low occurrence
of nausea and/or
vomiting, for example, where the side effects are observed in 35% or less of
the patients,
particularly 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less
of the patients;
- methods of treating amyloidosis, inhibiting or preventing amyloid deposition
and/or
treating or preventing an amyloid-related disease in a patient in need thereof
comprising
administering a formulation as described herein;
- methods for treating an A~i-related disease in a patient in need thereof
comprising
administering a formulation as described herein;
- methods for lowering levels of A(31-39, A(31-40, A(31-41, Aril-42, and/or
A(31-43,
particularly A(31-42, in the cerebrospinal fluid and/or plasma of a patient
which comprises
orally administering to the patient a formulation as described herein;
- methods for lowering the ratio of A(31-42 to A(31-40 levels in the
cerebrospinal fluid
and/or plasma of a patient which comprises orally administering to the patient
a formulation
as described herein;
- methods for stabilizing cognitive function or decreasing the rate of decline
in
cognitive function (for example, as assessed by Clinical Dementia Rating (CDR)
scale, Mini-
mental State Examination (MMSE), or Alzheimer's Disease Assessment Scale-
Cognitive
Subscale (ADAS-Cog)) in a patient in need thereof comprising administering a
formulation
as described herein;
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- methods of lessening gastrointestinal side effects in a human patient which
occur
from orally administering an active agent which is 3-amino-1-propanesulfonic
acid or a
pharmaceutically acceptable salt thereof, comprising administering said agent
according to a
schedule wherein an initial dose is administered and the dose is increased
over time to a
S higher dose which treats amyloidosis, inhibits or prevents amyloid
deposition and/or treats or
prevents an amyloid-related disease, for example: where the formulation is
administered in an
initial dose for one month followed by an increased dose the second month,
which is
optionally maintained throughout the treatment, or is followed by an increased
dose for the
third month which is maintained throughout the treatment, such as wherein the
patient is
administered 50 mg doses in the first month and 100 mg doses in the second and
following
months of treatment or wherein the patient is administered 50 mg doses in the
first month,
100 mg doses in the second month and 150 mg doses in the third and following
months of
treatment; said doses may, for example, be administered once or twice daily;
- any of the methods described herein which further comprises administering
another
therapeutic agent, for example, another agent which is effective for treating
amyloidosis,
inhibiting or preventing amyloid deposition and/or treating or preventing an
amyloid-related
disease, examples of which are discussed below;
- any of the methods described herein wherein the active agent is administered
in
doses of about 25 to about 200 mg, preferably about 50 to about 150 mg, more
preferably
about 50, about 100 or about 150 mg, and, preferably, daily or twice daily, or
lower or higher
amounts.
In other aspects, these methods involve administration to a patient in need of
treatment of amyloidosis, inhibitlon or prevention of amyloid deposition
and/or treatment or
prevention of an amyloid-related disease, more preferably wherein said
administration is to a
patient in need of treatment for an A(3-related disease, e.g., Alzheimer's
disease ("AD") and/or
cerebral amyloid angiopathy ("CAA"), particularly AD.
Another aspect is a method for treating a patient having Alzhiemer's disease
("AD") or
preventing or slowing the development of AD in a patient comprising
administering any of
the formulations discussed herein.
In other aspects, the invention is directed to formulations and methods for
treatment,
as described above, wherein the active agent is 3-amino-1-propanesulfonic acid
or a
pharmaceutically acceptable salt thereof provided in a modified release
formulation. The
modified release formulation is such that, for example:
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~ the formulation lessens the gastrointestinal side effects in a human patient
which
occur from administration of the active agent in an immediate release dosage
form,
~ the formulation includes an enteric coating,
~ the formulation includes a pharmaceutically acceptable vehicle which
modifies the
release of the active agent, which is different from an enteric coating and is
used
with or without an enteric coating,
~ the formulation is in a form for osmotic release, pulsatile release,
sustained
release, controlled release, delayed release, extended release or other
modified
release of the active agent,
~ the formulation is effective to lessen the increase in pH of the stomach
when
administered compared to that which occurs when said agent is administered in
an
immediate release dosage form,
~ the formulation comprises an effective amount of said agent to inhibit or
prevent
amyloid deposition and/or treat or prevent an amyloid-related disease and a
pharmaceutically acceptable vehicle,
~ the formulation comprises an effective amount of the active agent to treat
or
prevent an Aø-related disease, such as AD and/or CAA,
~ the formulation is effective for stabilizing cognitive function or
decreasing the rate
of decline in cognitive function (for example, as assessed by Clinical
Dementia
Rating (CDR) scale, Mini-mental State Examination (lVflVISE), or Alzheimer's
Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)) in a patient,
~ the formulation is effective to treat amyloidosis, inhibit or prevent
amyloid
deposition and/or treat or prevent an amyloid-related disease with lesser side
effects
in comparison to those which occur when said active agent is administered in
an
immediate release dosage form,
~ the formulation is effective to lower levels of Aø1-39, A(31-40, Aø1-41,
A(31-42,
and/or Aø1-43 in the cerebrospinal fluid and/or the plasma of a patient,
particularly
to lower Aø1-40 and/or Aø1-42, most particularly, Aø1-42, or
~ the formularion is effective to lower the ratio of the levels Aø1-42 to Aø1-
40 in
the cerebrospinal fluid and/or the plasma of a patient,
~ any combination of the above aspects.
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Detailed Description of the Invention
This invention pertains to methods, compositions, and formulations useful for
treating
amyloidosis. The methods of the invention involve administering to a subject a
therapeutic
formulation comprising a therapeutic compound that inhibits amyloid
deposition. In
particular, the present invention therefore relates to the use of therapeutic
formulations, e.g.,
comprising alkylsulfonic acids, in the prevention or treatment of amyloid-
related diseases,
including, inter alia, Alzheimer's disease, cerebral amyloid angiopathy,
inclusion body
myositis, macular degeneration, Down's syndrome, Mild Cognitive Impairment,
and type II
diabetes.
1. Amyloid-Related Diseases
The present invention relates to the use of pharmaceutical compositions or
formulations comprising therapeutic compounds useful in the treatment of
amyloid-related
diseases. Many amyloid-related diseases are known, and others doubtless exist.
AA (Reactive) Amyloidosis
Generally, AA amyloidosis is a manifestation of a number of diseases that
provoke a
sustained acute phase response. Such diseases include chronic inflammatory
disorders,
chronic local or systemic microbial infections, and malignant neoplasms. The
most common
form of reactive or secondary (AA) amyloidosis is seen as the result of long-
standing
inflammatory conditions. For example, patients with Rheumatoid Arthritis or
Familial
Mediterranean Fever (which is a genetic disease) can develop AA amyloidosis.
The terms
"AA amyloidosis" and "secondary (AA) amyloidosis" are used interchangeably.
AA fibrils are generally composed of 8,000 Dalton fragments (AA peptide or
protein)
formed by proteolytic cleavage of serum amyloid A protein (ApoSAA), a
circulating
apolipoprotein which is mainly synthesized in hepatocytes in response to such
cytokines as
IL-1,1L-6 and TNF. Once secreted, ApoSAA is complexed with I-iDL. Deposition
of AA
fibrils can be widespread in the body, with a preference for parenchyma)
organs. The kidneys
are usually a deposition site, and the liver and the spleen may also be
affected. Deposition is
also seen in the heart, gastrointestinal tract, and the skin.
Underlying diseases which can lead to the development of AA amyloidosis
include,
but are not limited to inflammatory diseases, such as rheumatoid arthritis,
juvenile chronic
arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's
syndrome, Adult
Still's disease, Behcet's syndrome, and Crohn's disease. AA deposits are also
produced as a
result of chronic microbial infections, such as leprosy, tuberculosis,
bronchiectasis, decubitus
ulcers, chronic pyelonephritis, osteomyelitis, and Whipple's disease. Certain
malignant
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neoplasms can also result in AA fibril amyloid deposits. These include such
conditions as
Hodgkin's lymphoma, renal carcinoma, carcinomas of gut, lung and urogenital
tract, basal
cell carcinoma, and hairy cell leukemia. Other underlying conditions that may
be associated
with AA amyloidosis are Castleman's disease and Schnitzler's syndrome.
AL Amyloidoses (Primary Amyloidosis)
AL amyloid deposition is generally associated with almost any dyscrasia of the
B
lymphocyte lineage, ranging from malignancy of plasma cells (multiple myeloma)
to benign
monoclonal gammopathy. At times, the presence of amyloid deposits may be a
primary
indicator of the underlying dyscrasia. AL amyloidosis is also described in
detail in Current
Drug Targets, 2004, S 159-171.
Fibrils of AL amyloid deposits are composed of monoclonal immunoglobulin light
chains or fragments thereof. More specifically, the fragments are derived from
the N-terminal
region of the light chain (kappa or lambda) and contain all or part of the
variable (VL) domain
thereof. Deposits generally occur in the mesenchymal tissues, causing
peripheral and
autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive
cardiomyopathy,
arthropathy of large joints, immune dyscrasias, myelomas, as well as occult
dyscrasias.
However, it should be noted that almost any tissue, particularly visceral
organs such as the
kidney, liver, spleen and heart, may be involved.
Hereditary Systemic Amyloidoses
There are many foams of hereditary systemic amyloidoses. Although they are
relatively rare conditions, adult onset of symptoms and their inheritance
patterns (usually
autosomal dominant) lead to persistence of such disorders in the general
population.
Generally, the syndromes are attributable to point mutations in the precursor
protein leading
to production of variant amyloidogenic peptides or proteins. Table 1
summarizes the fibril
composition of exemplary forms of these disorders.
TABLE 1 - Fibril Composition of Exemplary Amyloid-Related Diseases
Fibril Peptide/Protein Genetic Clinical Syndrome
Variant
ATTR protein from TransthyretinMet30, manyFamilial amyloid polyneuropathy
(FAP),
and fragments others (Mainly peripheral nerves)
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_.~ .. ,. ... . . ..... .
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Fibril PeptidelProtein Genetic Clinical Syndrome
Variant
ATTR protein from TransthyretinThr45, Cardiac involvement predominant
A1a60, without
and fragments Ser84, neuropathy, familial amyloid
Metl l polyneuropathy,
l,
I1e122 senile systemic amyloidosis,
Tenosynovium
N-terminal fragment Arg26 Familial amyloid polyneuropathy
of (FAP),
Apolipoprotein A1 (apoAI) (mainly peripheral nerves)
N-terminal fragment Arg26, Ostertag-type, non-neuropathic
of Arg50, (predominantly
Apoliproprotein A1 (AapoAI)Arg 60, visceral involvement)
others
AapoAII from Apolipoprotein Familial amyloidosis
All
Lysozyme (Alys) Thr56, Ostertag-type, non-neuropathic
His67 (predominantly
visceral involvement)
Fibrogen alpha chain Leu554, Cranial neuropathy with lattic
fragment Val corneal
526 dystrophy
Gelsolin fragment (Agel)Asn187, Cranial neuropathy with lattice
corneal
Tyr187 dystrophy
Cystatin C fragment G1u68 Hereditary cerebral hemorrhage
(ACys) (cerebral
amyloid angiopathy) - Icelandic
type
(3-amyloid protein (A(3)G1n693 Hereditary cerebral hemorrhage
derived from (cerebral
Amyloid Precursor Protein amyloid angiopathy) - Dutch
(APP) type
~i-amyloid protein (A~i)I1e717, Familial Alzheimer's Disease
derived from Phe717,
Amyloid Precursor ProteinG1y717
(APP)
(3-amyloid protein (A(3)Gln 618 Alzheimer's disease, Down's
derived from syndrome,
Amyloid Precursor Protein hereditary cerebral hemorrhage
(APP), with
e.g., bPP 695 amyloidosis, Dutch type
(3-amyloid protein (A(3)Asn670, Familial Dementia - probably
derived from Alzheimer's
Amyloid Precursor ProteinLeu671 Disease
(APP)
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Fibril Peptide/Protein Genetic Clinical Syndrome
Variant
Prion Protein (PrP, Leu102, Familial Creutzfeldt-Jakob
APrPs~) derived disease;
from Prp precursor proteinVa1167, Gerstmann-Str~ussler-Scheinker
(51-91 syndroxrte
insert) Asn178, (hereditary spongiform encephalopathies,
Lys200 prion diseases)
AA derived from Serum Familial Mediterranean fever,
amyloid A predominant
protein (ApoSAA) renal involvement (autosomal
recessive)
AA derived from Serum Muckle-Well's syndrome, nephropathy,
amyloid A
protein (ApoSAA) deafness, urticaria, limb
pain
Unknown Cardiomyopathy with persistent
atrial
standstill
Unknown Cutaneous deposits (bullous,
papular,
pustulodermal)
AH amyloid protein, Ay I Myeloma associated amyloidosis
derived from
immunoglobulin heavy
chain
(gI)
ACaI amyloid protein (Pro) calcitoninMedullary carcinomas of the
from thyroid
(pro)calcitonin
AANF amyloid protein Isolated atrial amyloid
from atrial
natriuredc factor
Apro from Prolactin Prolactinomas
Abri/ADan from ABri British and Danish familial
peptide Dementia
uata aenvea from a an ~ x, repys Mi3. Amyloidosis. Histopathology, 25(S), 403-
414 (Nov 1994), WHO/IUIS
Nomenclature Subcommittee, Nomenclature of Amyloid and Amyloidosis. Bulletin
of the World Health
Organisation 1993; 71: 10508; and Merlini et al., Clin Chem Lab Med 2001;
39(11): 1065-75.
The data provided in Table 1 are exemplary and are not intended to limit the
scope of
the invention. For example, more than 40 separate point mutations in the
transthyretin gene
have been described, all of which give rise to clinically similar forms of
familial amyloid
polyneuropathy.
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In general, any hereditary amyloid disorder can also occur sporadically, and
both
hereditary and sporadic forms of a disease present with the same
characteristics with regard to
amyloid. For example, the most prevalent form of secondary AA amyloidosis
occurs
sporadically, e.g., as a result of ongoing inflammation, and is not associated
with Familial
Mediterranean Fever. Thus general discussion relating to hereditary amyloid
disorders below
can also be applied to sporadic amyloidoses.
Transthyretin (TTR) is a 14 kiloDalton protein that is also sometimes referred
to as
prealbumin. It is produced by the liver and choroid plexus, and it functions
in transporting
thyroid hormones and vitamin A. At least 50 variant forms of the protein, each
characterized
by a single amino acid change, are responsible for various forms of familial
amyloid
polyneuropathy. For example, substitution of proline for leucine at position
55 results in a
particularly progressive form of neuropathy; substitution of methionine for
leucine at position
111 resulted in a severe cardiopathy in Danish patients.
Amyloid deposits isolated from heart tissue of patients with systemic
amyloidosis
have revealed that the deposits are composed of a heterogeneous mixture of TTR
and
fragments thereof, collectively referred to as ATTR, the full length sequences
of which have
been characterized. ATTR fibril components can be extracted from such plaques
and their
structure and sequence determined according to the methods known in the art
(e.g.,
Gustavsson, A., et al., Laboratory Invest. 73: 703-708, 1995; Kametani, F., et
al., Biochem.
Biophys. Res. Commun. 125: 622-628, 1984; Pras, M., et al., PNAS 80: 539-42,
1983).
Persons having point mutations in the molecule apolipoprotein A1 (e.g.,
Gly~Arg26;
Trp~Arg50; Leu-~Arg60) exhibit a form of amyloidosis ("Ostertag type")
characterized by
deposits of the protein apolipoprotein AI or fragments thereof (AApoAn. These
patients
have low levels of high density lipoprotein (ILL) and present with a
peripheral neuropathy or
renal failure.
A mutation in the alpha chain of the enzyme lysozyme (e.g., Ile~Thr56 or
Asp~His57) is the basis of another form of bstertag-type non-neuropathic
hereditary
amyloid reported in English families. Here, fibrils of the mutant lysozyme
protein (Alys) are
deposited, and patients generally exhibit impaired renal function. This
protein, unlike most of
the fibril-forming proteins described herein, is usually present in whole
(unfragmented) form
(Benson, M.D., et al. CIBA Fdn. Symp. 199: 104-131, 1996).
Immunoglobulin light chains tend to form aggregates in various morphologies,
including fibrillar (e.g., AL amyloidosis and AH amyloidosis), granular (e.g.,
light chain
deposition disease (LCDD), heavy chain deposition disease (HCDD), and light-
heavy chain
deposition disease (LHCDD)), crystalline (e.g., Acquired Farconi's Syndome),
and
microtubular (e.g., Cryoglobulinemia). AL and AH amyloidosis is indicated by
the formation
of insoluble fibrils of immunoglobulin light chains and heavy chain,
respectively, and/or their
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fragments. In AL fibrils, lambda (~,) chains such as ~, VI chains (7~,6
chains), are found in
greater concentrations than kappa (x) chains. ,III chains are also slightly
elevated. Merlini et
al., CLIN CHEM LAB MEn 39(11):1065-75 (2001). Heavy chain amyloidosis (AH) is
generally
characterized by aggregates of gamma chain amyloid proteins of the IgGl
subclass. Eulitz et
al., PROC NATL ACRD ScI USA 87:6542-46 (1990).
Comparison of amyloidogenic to non-amyloidogenic light chains has revealed
that the
former can include replacements or substitutions that appear to destabilize
the folding of the
protein and promote aggregation. AL and LCDD have been distinguished from
other amyloid
diseases due to their relatively small population monoclonal light chains, or
fragments
thereof, which are manufactured by neoplastic expansion of an antibody-
producing B cell.
AL aggregates typically are well-ordered fibrils of lambda chains. LCDD
aggregates are
relatively amorphous aggregations of both kappa and lambda chains, with a
majority being
kappa, in some cases xIV. Bellotti et al., JOURNAL OF STRUCTURAL BIOLOGY
13:280-89
(2000). Comparison of amyloidogenic and non-amyloidogenic heavy chains in
patients
having AH amyloidosis has revealed missing and/or altered components. Eulitz
et al., PROC
NATL ACAD SCI USA 87:6542-46 (1990) (pathogenic heavy chain characterized by
significantly lower molecular mass than non-amyloidogenic heavy chains); and
Solomon et
al. Alvt J HEMAT 45(2) 171-6 (1994) (amyloidogenic heavy chain characterized
as consisting
solely of the VH-D portion of the non-amyloidogenic heavy chain).
Accordingly, potential methods of detecting and monitoring treatment of
subjects
having or at of having AL, LCDD, AH, and the like, include but are not limited
to
immunoassaying plasma or urine for the presence or depressed deposition of
amyloidogenic
light or heavy chains, e.g., amyloid a,, amyloid x, amyloid xIV, amyloid ~y,
or amyloid ~yl.
Brain Amyloidosis
The most frequent type of amyloid in the brain is composed primarily of A(3
peptide
fibrils, resulting in dementia associated with sporadic (non-hereditary)
Alzheimer's disease.
In fact, the incidence of sporadic Alzheimer's disease greatly exceeds forms
shown to be
hereditary. Nevertheless, fibril peptides forming plaques are very similar in
both types. Brain
amyloidosis includes those diseases, conditions, pathologies, and other
abnormalities of the
structure or function of the brain, including components thereof, in which the
causative agent
is amyloid. The area of the brain affected in an amyloid-related disease may
be the stroma
including the vasculature or the parenchyma including functional or anatomical
regions, or
neurons themselves. A subject need not have received a definitive diagnosis of
a specifically
recognized amyloid-related disease. The term "amyloid-related disease"
includes brain
amyloidosis.
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Amyloid-(3 peptide ("A(3") is a 39-43 amino acid peptide derived by
proteolysis from
a large protein known as Beta Amyloid Precursor Protein ("(3APP"). Mutations
in (3APP
result in familial forms of Alzheimer's disease, Down's syndrome, cerebral
amyloid
angiopathy, and senile dementia, characterized by cerebral deposition of
plaques composed of
A(3 fibrils and other components, which are described in further detail below.
Known
mutations in APP associated with Alzheimer's disease occur proximate to the
cleavage sites
of (3 or y-secretase, or within A(3. For example, position 717 is proximate to
the site of
gamma-secretase cleavage of APP in its processing to A(3, and positions
670/671 are
proximate to the site of ~i-secretase cleavage. Mutations at any of these
residues may result in
Alzheimer's disease, presumably by causing an increase in the amount of the
42/43 amino
acid form of A(3 generated from APP. The familial form of Alzheimer's disease
represents
only 10% of the subject population. Most occurrences of Alzheimer's disease
are sporadic
cases where APP and A(3 do not possess any mutation. The structure and
sequence of A(3
peptides of various lengths are well known in the art. Such peptides can be
made according to
methods known in the art, or extracted from the brain according to known
methods (e.g.,
Glenner and Wong, Biochem. Biophys. Res. Comm. 129, 885-90 (1984); Glenner and
Wong,
Biochem. Biophys. Res. Comm. 122, 1131-35 (1984)). In addition, various forms
of the
peptides are commercially available. APP is expressed and constitutively
catabolized in most
cells. The dominant catabolic pathway appears to be cleavage of APP within the
A(3
sequence by an enzyme provisionally termed a-secretase, leading to release of
a soluble
ectodomain fragment known as APPsa. This cleavage precludes the formation of
A(3 peptide.
In contrast to this non-amyloidogenic pathway, APP can also be cleaved by
enzymes known
as (3- and y-secretase at the N- and C-termini of the A(3 , respectively,
followed by release of
A(3 into the extracellular space. To date, BACE has been identified as ~i-
secretase (Vasser,
et al., Science 286:735-741, 1999) and presenilins have been implicated in y-
secretase activity
(De Strooper, et al., Nature 391, 387-90 (1998)). The 39-43 amino acid A(3
peptide is
produced by sequential proteolytic cleavage of the amyloid precursor protein
(APP) by the (3
and y secretases enzyme. Although A~i40 is the predominant form produced, 5-7%
of total A(3
exists as A(342 (Cappai et al., Int. J. Biochem. Cell Biol. 31. 885-89
(1999)).
The length of the A(3 peptide appears to dramatically alter its
biochemical/biophysical
properties. Specifically, the additional two amino acids at.the C-terminus of
A(342 are very
hydrophobic, presumably increasing the propensity of A(342 to aggregate. For
example,
Jarrett, et al. demonstrated that A(342 aggregates very rapidly in vitro
compared to A(340,
suggesting that the longer forms of A(3 may be the important pathological
proteins that are
involved in the initial seeding of the neuritic plaques in Alzheimer's disease
(Jarrett, et al.,
Biochemistry 32, 4693-97 (1993); Jarrett, et al., Ann. N. Y. Acad. Sci. 695,
144-48 (1993)).
This hypothesis has been further substantiated by the recent analysis of the
contributions of
specific forms of A(3 in cases of genetic familial forms of Alzheimer's
disease ("FAD"). For
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example, the "London" mutant form of APP (APPV7171) linked to FAD selectively
increases
the production of A~3 42/43 forms versus A(3 40 (Suzuki, et al., Science 264,
1336-40 (1994))
while the "Swedish" mutant form of APP (APPK670N/M671L) increases levels of
both
A(340 and A~342/43 (Citron, et al., Nature 360, 672-674 (1992); Cai, et al.,
Science 259,
514-16, (1993)). Also, it has been observed that FAD-linked mutations in the
Presenilin-1
("PS 1") or Presenilin-2 ("PS2") genes will lead to a selective increase in
A(342/43 production
but not A~i40 (Borchelt, et al., Neuron 17, 1005-13 (1996)). This finding was
corroborated in
transgenic mouse models expressing PS mutants that demonstrate a selective
increase in brain
A~342 (Borchelt, op cit.; Duff, et al., Neurodegeneration 5(4), 293-98
(1996)). Thus the
leading hypothesis regarding the etiology of Alzheimer's disease is that an
increase in A[~42
brain concentration due to an increased production and release of A(342 or a
decrease in
clearance (degradation or brain clearance) is a causative event in the disease
pathology.
Multiple mutation sites in either A~i or the APP gene have been identified and
are
clinically associated with either dementia or cerebral hemorrhage. Exemplary
CAA disorders
include, but are not limited to, hereditary cerebral hemorrhage with
amyloidosis of Icelandic
type (HCHWA-1); the Dutch variant of HCHWA (HCHWA-D; a mutation in A~i); the
Flemish mutation of A~i; the Arctic mutation of A(i; the Italian mutation of
A(i; the Iowa
mutation of A~i; familial British dementia; and familial Danish dementia. CAA
may also be
sporadic.
As used herein, the terms "(3 amyloid," "amyloid-[3," and the like refer to
amyloid (3
proteins or peptides, amyloid (3 precursor proteins or peptides,
intermediates, and
modifications and fragments thereof, unless otherwise specifically indicated.
In particular,
"A(i" refers to any peptide produced by proteolytic processing of the APP gene
product,
especially peptides which are associated with amyloid pathologies, including
A~31-39,
A(31-40, A(31-41, A(31-42, and A(31-43. For convenience of nomenclature, "A(31-
42" may be
referred to herein as "A(3(1-42)" or simply as "A(342" or "A(342" (and
likewise for any other
amyloid peptides discussed herein). As used herein, the terms "~i amyloid,"
"amyloid-(3," and
"A~i" are synonymous.
Unless otherwise specified, the term "amyloid" refers to amyloidogenic
proteins,
peptides, or fragments thereof which can be soluble (e.g., monomeric or
oligomeric) or
insoluble (e.g., having fibrillary structure or in amyloid plaque). See, e.g.,
MP Lambert, et al.,
Proc. Nat'l Acad. Sci. USA 95, 6448-53 (1998). "Amyloidosis" or "amyloid
disease" or
"amyloid-related disease" refers to a pathological condition characterized by
the presence of
amyloid fibers. "Amyloid" is a generic term refernng to a group of diverse but
specific
protein deposits (intracellular or extracellular) which are seen in a number
of different
diseases. Though diverse in their occurrence, all amyloid deposits have common
morphologic
properties, stain with specific dyes (e.g., Congo red), and have a
characteristic red-green
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birefringent appearance in polarized light after staining. They also share
common
ultrastructural features and common X-ray diffraction and infrared spectra.
Gelsolin is a calcium binding protein that binds to fragments and actin
filaments.
Mutations at position 187 (e.g., Asp-~Asn; Asp-~Tyr) of the protein result in
a form of
hereditary systemic amyloidosis, usually found in patients from Finland, as
well as persons of
Dutch or Japanese origin. In afflicted individuals, fibrils formed from
gelsolin fragments
(Agel), usually consist of amino acids 173-243 (68 kDa carboxyterminal
fragment) and are
deposited in blood vessels and basement membranes, resulting in corneal
dystrophy and
cranial neuropathy which progresses to peripheral neuropathy, dystrophic skin
changes and
deposition in other organs. (Kangas, H., et al. Human Mol. Genet. 5(9): 1237-
1243, 1996).
Other mutated proteins, such as mutant alpha chain of fibrinogen (AfibA) and
mutant
cystatin C (Acys) also form fibrils and produce characteristic hereditary
disorders. AfibA
fibrils form deposits characteristic of a nonneuropathic hereditary amyloid
with renal disease;
Acys deposits are characteristic of a hereditary cerebral amyloid angiopathy
reported in
Iceland (Isselbacher, Harrison's Principles of Internal Medicine, McGraw-Hill,
San
Francisco, 1995; Benson, et al.). In at least some cases, patients with
cerebral amyloid
angiopathy (CAA) have been shown to have amyloid fibrils containing a non-
mutant form of
cystatin C in conjunction with amyloid beta protein (Nagai, A., et al. Molec.
Chem.
Neuropathol. 33: 63-78, 1998).
Certain forms of prion disease are now considered to be heritable, accounting
for up to
15% of cases, which were previously thought to be predominantly infectious in
nature.
(Baldwin, et al., in Research Advances in Alzheimer's Disease and Related
Disorders, John
Wiley and Sons, New York, 1995). In hereditary and sporadic prion disorders,
patients
develop plaques composed of abnormal isoforms of the normal prion protein
(PrPs~).
A predominant mutant isoform, PrPs~, also referred to as AScr, differs from
the
normal cellular protein in its resistance to protease degradation,
insolubility after detergent
extraction, deposition in secondary lysosomes, post-translational synthesis,
and high
~3-pleated sheet content. Genetic linkage has been established for at least
five mutations
resulting in Creutzfeldt-Jacob disease (CJD), Gerstmann-Straussler-Scheinker
syndrome
(GSS), and fatal familial insomnia (FFI). (Baldwin, supra) Methods for
extracting fibril
peptides from scrapie fibrils, determining sequences and making such peptides
are known in
the art (e.g., Beekes, M., et al. J. Gen. Virol. 76: 2567-76, 1995).
For example, one form of GSS has been linked to a PrP mutation at codon 102,
while
telencephalic GSS segregates with a mutation at codon 117. Mutations at codons
198 and 217
result in a form of GSS in which neuritic plaques characteristic of
Alzheimer's disease
contain PrP instead of A(3 peptide. Certain forms of familial CJD have been
associated with
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mutations at codons 200 and 210; mutations at codons 129 and 178 have been
found in both
familial CJD and FFI. (Baldwin, supra).
Cerebral Amyloidosis
Local deposition of amyloid is common in the brain, particularly in elderly
individuals. The most frequent type of amyloid in the brain is composed
primarily of A~3
peptide fibrils, resulting in dementia or sporadic (non-hereditary)
Alzheimer's disease. The
most common occurrences of cerebral amyloidosis are sporadic and not familial.
For
example, the incidence of sporadic Alzheimer's disease and sporadic CAA
greatly exceeds
the incidence of familial AD and CAA. Moreover, sporadic and familial forms of
the disease
cannot be distinguished from each other (they differ only in the presence or
absence of an
inherited genetic mutation); for example, the clinical symptoms and the
amyloid plaques
formed in both sporadic and familial AD are very similar, if not identical.
Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid
fibrils
in the walls of leptomingeal and cortical arteries, arterioles and veins. It
is commonly
associated with Alzheimer's disease, Down's syndrome and normal aging, as well
as with a
variety of familial conditions related to stroke or dementia (see Frangione et
al., Amyloid: J.
Protein Folding Disord. 8, Suppl. 1, 36-42 (2001)). CAA can occur sporadically
or be
hereditary.
Senile Systemic Amyloidosis
Amyloid deposition, either systemic or focal, increases with age. For example,
fibrils
of wild type transthyretin (TTR) are commonly found in the heart tissue of
elderly
individuals. These may be asymptomatic, clinically silent, or may result in
heart failure.
Asymptomatic fibrillar focal deposits may also occur in the brain (A(3),
corpora amylacea of
the prostate ((32 microglobulin), joints and seminal vesicles.
Dialysis-related Amyloidosis (DRA)
Plaques composed of (32 microglobulin ((izM) fibrils commonly develop in
patients
receiving long term hemodialysis or peritoneal dialysis. (32 microglobulin is
a 11.8 kiloDalton
polypeptide and is the light chain of Class I MHC antigens, which are present
on all nucleated
cells. Under normal circumstances, /32M is usually distributed in the
extracellular space
unless there is an impaired renal function, in which case (32M is transported
into tissues where
it polymerizes to form amyloid fibrils. Failure of clearance such as in the
case of impaired
renal function, leads to deposition in the carpal tunnel and other sites
(primarily in collagen-
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rich tissues of the joints). Unlike other fibril proteins, ~i2M molecules are
not produced by
cleavage of a longer precursor protein and are generally present in
unfragmented form in the
fibrils. (Benson, supra). Retention and accumulation of this amyloid precursor
has been
shown to be the main pathogenic process underlying DRA. DRA is characterized
by
peripheral joint osteoarthropathy (e.g., joint stiffness, pain, swelling,
etc.). Isoforms of ~i2M,
glycated (32M, or polymers of (32M ih tissue are the most amyloidogenic form
(as opposed to
native ~i2M). Unlike other types of amyloidosis, (32M is confined largely to
osteoarticular
sites. Visceral depositions are rare. Occasionally, these deposits may involve
blood vessels
and other important anatomic sites.
Despite improved dialysis methods for removal of ~i2M, the majority of
patients have
plasmatic [32M concentrations that remain dramatically higher than normal.
These elevated
(32M concentrations generally lead to Diabetes-Related Amyloidosis (DRA) and
cormorbidities that contribute to mortality.
Islet Amyloid Polypeptide and Diabetes
Islet hyalinosis (amyloid deposition) was first described over a century ago
as the
presence of fibrous protein aggregates in the pancreas of patients with severe
hyperglycemia
(Opie, EL., J Exp. Med. 5: 397-428, 1901). Today, islet amyloid, composed
predominantly of
islet amyloid polypeptide (IAPP), or amylin, is a characteristic
histopathological marker in
over 90% of all cases of Type II diabetes (also known as Non-Insulin Dependent
Diabetes, or
NIDDM). These fibrillar accumulations result from the aggregation of the islet
amyloid
polypeptide (IAPP) or amylin, which is a 37 amino acid peptide, derived from a
larger
precursor peptide, called pro-IAPP.
IAPP is co-secreted with insulin in response to (3-cell secretagogues. This
pathological feature is not associated with insulin-dependent (Type I)
diabetes and is a
unifying characteristic for the heterogeneous clinical phenotypes diagnosed as
NIDDM (Type
II diabetes).
Longitudinal studies in cats and immunocytochemical investigations in monkeys
have
shown that a progressive increase in islet amyloid is associated with a
dramatic decrease in
the population of insulin-secreting ~i-cells and increased severity of the
disease. More
recently, transgenic studies have strengthened the relationship between IAPP
plaque
formation and ~i-cell apoptosis and dysfunction, indicating that amyloid
deposition is a
principal factor in increasing severity of Type II diabetes.
IAPP has also been shown to induce (3-islet cell toxicity in vitro, indicating
that
appearance of IAPP fibrils in the pancreas of Type II or Type I diabetic
patients (post-islet
transplantation) could contribute to the loss of the (3-cell islets
(Langerhans) and organ
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dysfunction. In patients with Type II diabetes, the accumulation of pancreatic
IAPP leads to
formation of oligomeric IAPP, leading to a buildup of IAPP-amyloid as
insoluble fibrous
deposits which eventually destroys the insulin-producing ~i cells of the
islet, resulting in (3 cell
depletion and failure (Westermark, P., Grimelius, L., Acta Path. Microbiol.
Scand., sect. A.
81: 291-300, 1973; de Koning, EJP., et al., Diabetologia 36: 378-384, 1993;
and Lorenzo, A.,
et ad., Nature 368: 756-760, 1994). Accumulation of IAPP as fibrous deposits
can also have
an impact on the ratio of pro-IAPP to IAPP normally found in plasma by
increasing this ratio
due to the trapping of IAPP in deposits. Reduction of ~i cell mass can be
manifested by
hyperglycemia and insulinemia. This (3-cell mass loss can lead to a need for
insulin therapy.
Diseases caused by the death or malfunctioning of a particular type or types
of cells
can be treated by transplanting into the patient healthy cells of the relevant
type of cell. This
approach has been used for Type I diabetes patients. Often pancreatic islet
cells from a donor
are cultured in vitro prior to transplantation, to allow them to recover after
the isolation
procedure or to reduce their immunogenicity. However, in many instances islet
cell
transplantation is unsuccessful, due to death of the transplanted cells. One
reason for this
poor success rate is IAPP, which organizes into toxic oligomers. Toxic effects
may result
from intracellular and extracellular accumulation of fibril oligomers. The
IAPP oligomers
can form fibrils and become toxic to the cells in vitro. In addition, LAPP
fibrils are likely to
continue to grow after the cells are transplanted and cause death or
dysfunction of the cells.
This may occur even when the cells are from a healthy donor and the patient
receiving the
transplant does not have a disease that is characterized by the presence of
fibrils. For
example, compounds of the present invention may also be used in preparing
tissues or cells
for transplantation according to the methods described in International Patent
Application
(PCT) number WO 01/003680.
The compounds of the invention may also stabilize the ratio of the
concentrations of
Pro-IAPP/IAPP, pro-Insulin/Insulin and C-peptide levels. In addition, as
biological markers
of efficacy, the results of the different tests, such as the arginine-insulin
secretion test, the
glucose tolerance test, insulin tolerance and sensitivity tests, could all be
used as markers of
reduced (3-cell mass and/or accumulation of amyloid deposits. Such class of
drugs could be
used together with other drugs targeting insulin resistance, hepatic glucose
production, and
insulin secretion. Such compounds might prevent insulin therapy by preserving
/3-cell
function and be applicable to preserving islet transplants.
Hormone-derived Amyloidoses
Endocrine organs may harbor amyloid deposits, particularly in aged
individuals.
Hormone-secreting tumors may also contain hormone-derived amyloid plaques, the
fibrils of
which are made up of polypeptide hormones such as calcitonin (medullary
carcinoma of the
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thyroid), and atrial natriuretic peptide (isolated atrial amyloidosis).
Sequences and structures
of these proteins are well known in the art.
Miscellaneous Amyloidoses
There are a variety of other forms of amyloid disease that are normally
manifest as
localized deposits of amyloid. In general, these diseases are probably the
result of the
localized production or lack of catabolism of specific fibril precursors or a
predisposition of a
particular tissue (such as the joint) for fibril deposition. Examples of such
idiopathic
deposition include nodular AL amyloid, cutaneous amyloid, endocrine amyloid,
and
tumor-related amyloid. Other amyloid-related diseases include those described
in Table 1,
such as familial amyloid polyneuropathy (FAP), senile systemic amyloidosis,
Tenosynovium,
familial amyloidosis, Ostertag-type, non-neuropathic amyloidosis, cranial
neuropathy,
hereditary cerebral hemorrhage, familial dementia, chronic dialysis, familial
Creutzfeldt-Jakob disease; Gerstmann-Straussler-Scheinker syndrome, hereditary
spongiform
encephalopathies, prion diseases, familial Mediterranean fever, Muckle-Well's
syndrome,
nephropathy, deafness, urticaria, limb pain, cardiomyopathy, cutaneous
deposits, multiple
myeloma, benign monoclonal gammopathy, maccoglobulinaemia, myeloma associated
amyloidosis, medullary carcinomas of the thyroid, isolated atrial amyloid, and
diabetes.
The compounds of the invention may be administered therapeutically or
prophylactically to treat diseases associated with amyloid fibril formation,
aggregation or
deposition, regardless of the clinical setting. The compounds of the invention
may act to
ameliorate the course of an amyloid-related disease using any of the following
mechanisms,
such as, for example but not limited to: slowing the rate of amyloid fibril
formation or
deposition; lessening the degree of amyloid deposition; inhibiting, reducing,
or preventing
amyloid fibril formation; inhibiting amyloid induced inflammation; enhancing
the clearance
of amyloid from, for example, the brain; or protecting cells from amyloid
induced (oligomers
or fibrillar) toxicity.
In an embodiment, the compounds/formulations of the invention may be
administered
therapeutically or prophylactically to treat diseases associated with amyloid-
~i fibril
formation, aggregation or deposition. The compounds of the invention may act
to ameliorate
the course of an amyloid-(3 related disease using any of the following
mechanisms (this list is
meant to be illustrative and not limiting): slowing the rate of amyloid-(3
fibril formation or
deposition; lessening the degree of amyloid-(3 deposition; inhibiting,
reducing, or preventing
amyloid-~i fibril formation; inhibiting neurodegeneration or cellular toxicity
induced by
amyloid-(3; inhibiting amyloid-~i induced inflammation; enhancing the
clearance of amyloid-(3
from the brain; or favoring greater catabolism of A~i.
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Compounds of the invention may be effective in controlling amyloid-(3
deposition
either following their entry into the brain (following penetration of the
blood brain barrier) or
from the periphery. When acting from the periphery, a compound may alter the
equilibrium
of A(3 between the brain and the plasma so as to favor the exit of A(3 from
the brain. An
increase in the exit of A[3 from the brain would result in a decrease in A(i
brain concentration
and therefore favor a decrease in A(3 deposition. In addition, compounds that
penetrate the
brain may control deposition by acting directly on brain A(3, e.g., by
maintaining it in a
non-fibrillar form or favoring its clearance from the brain. The compounds may
slow down
APP processing; may increase degradation of A(3 fibrils by macrophages or by
neuronal cells;
or may decrease A(3 production by activated microglia. These compounds could
also prevent
A(3 in the brain from interacting with the cell surface and therefore prevent
neurotoxicity,
neurodegeneration, or inflammation.
In a preferred embodiment, the method is used to treat Alzheimer's disease
(e.g.,
sporadic or familial AD). The method can also be used prophylactically or
therapeutically to
treat other clinical occurrences of amyloid-(3 deposition, such as in Down's
syndrome
individuals and in patients with cerebral amyloid angiopathy ("CAA"),
hereditary cerebral
hemorrhage, or early Alzheimer's disease.
In another embodiment, the method is used to treat mild cognitive impairment.
Mild
Cognitive Impairment ("MCr') is a condition characterized by a state of mild
but measurable
impairment in thinking skills, which is not necessarily associated with the
presence of
dementia. MCI frequently, but not necessarily, precedes Alzheimer's disease.
Additionally, abnormal accumulation of APP and of amyloid-(3 protein in muscle
fibers has been implicated in the pathology of sporadic inclusion body
myositis (IBM)
(Askanas, V., et al. (1996) Proc. Natl. Acad. Sci. USA 93: 1314-1319; Askanas,
V. et al.
(1995) Current Opinion in Rheumatology 7: 486-496). Accordingly, the compounds
of the
invention can be used prophylactically or therapeutically in the treatment of
disorders in
which amyloid-beta protein is abnormally deposited at non-neurological
locations, such as
treatment of IBM by delivery of the compounds to muscle fibers.
Additionally, it has been shown that A(3 is associated with abnormal
extracellular
deposits, known as drusen, that accumulate along the basal surface of the
retinal pigmented
epithelium in individuals with age-related macular degeneration (ARMD). ARMD
is a cause
of irreversible vision loss in older individuals. It is believed that A(3
deposition could be an
important component of the local inflammatory events that contribute to
atrophy of the retinal
pigmented epithelium, drusen biogenesis, and the pathogenesis of ARMD
(Johnson, et al.,
Proc. Natl. Acad. Sci. USA 99(18), 11830-5 (2002)).
In another embodiment, the invention also relates to a method of treating or
preventing an amyloid-related disease in a subject (preferably a human)
comprising
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administering to the subject a therapeutic amount of a compound according to
the following
Formulae or otherwise described herein, such that amyloid fibril formation or
deposition,
neurodegeneration, or cellular toxicity is reduced or inhibited. In another
embodiment, the
invention relates to a method of treating or preventing an amyloid-related
disease in a subject
(preferably a human) comprising administering to the subject a therapeutic
amount of a
compound according to the following Formulae or otherwise described herein,
such that
cognitive function is improved or stabilized or further deterioration in
cognitive function is
prevented, slowed, or stopped in patients with brain amyloidosis, e.g.,
Alzheimer's disease,
Down's syndrome or cerebral amyloid angiopathy. These compounds can also
improve
quality of daily living in these subjects.
The therapeutic compounds of the invention may treat amyloidosis related to
type II
diabetes by, for example, stabilizing glycemia, preventing or reducing the
loss of ~i cell mass,
reducing or preventing hyperglycemia due to loss of ~i cell mass, and
modulating (e.g.,
increasing or stabilizing) insulin production. The compounds of the invention
may also
stabilize the ratio of the concentrations of pro-IAPP/IAPP.
The therapeutic compounds of the invention may treat AA (secondary)
amyloidosis
and/or AL (primary) amyloidosis, by stabilizing renal function, decreasing
proteinuria,
increasing creatinine clearance (e.g., by at least 50% or greater or by at
least 100% or greater),
or by leading to remission of chronic diarrhea, or weight gain (e.g., 10% or
greater).
11. Methods of the Invention
In one embodiment, the invention includes a method for inhibiting amyloid
deposition
in a subject comprising administering to the subject an effective amount of a
therapeutic
formulation comprising a therapeutic compound as described herein, such that
amyloid
deposition is inhibited. Accordingly, in another embodiment, the invention
pertains to a
method of treating or preventing an amyloid-related disease, e.g., A(3-related
disease, in a
subject comprising administering to a subject a therapeutic amount of a
therapeutic
formulation comprising a therapeutic compound of the invention.
The formulations of the invention may be administered therapeutically or
prophylactically to treat diseases associated with amyloid-(3 fibril
formation, aggregation or
deposition. The formulations of the invention may act to ameliorate the course
of an
amyloid-(3 related disease using any of the following mechanisms (this list is
meant to be
illustrative and not limiting): slowing the rate of amyloid-(3 fibril
formation or deposition;
lessening the degree of amyloid-(3 deposition; inhibiting, reducing, or
preventing amyloid-~3
fibril formation; inhibiting neurodegeneration or cellular toxicity induced by
amyloid-(3;
inhibiting amyloid-(3 induced inflammation; or enhancing the clearance of
amyloid-~i from the
brain.
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CA 02504471 2005-04-12
The formulations of the invention may be effective in controlling amyloid-~i
deposition either following their entry into the brain (following penetration
of the blood brain
barner) or from the periphery. Without wishing to be bound by theory, when
acting from the
periphery, the compound of a formulation of the invention may alter the
equilibrium of Ap
between the brain and the plasma so as to favor the exit of A~i from the
brain. An increase in
the exit of A~i from the brain would result in a decrease in A~i brain
concentration and
therefore favor a decrease in A~i deposition. Alternatively, the compounds of
a formulation of
the invention that penetrate the brain could control deposition by acting
directly on brain A~3,
e.g., by maintaining it in a non-fibrillar form or favoring its clearance from
the brain, or
protecting brain cells from the detrimental effect of A[3. In another
embodiment, the
compound may also prevent the amyloid protein, in its soluble, oligomeric form
or in its
fibrillar form, from binding or adhering to a cell surface and causing cell
damage or toxicity.
In a particular embodiment, the method is used to treat Alzheimer's disease
(e.g.,
sporadic or familial AD). The method can also be used prophylactically or
therapeutically to
treat other clinical occurrences of amyloid-~i deposition, such as in Down's
syndrome
individuals and in patients with cerebral amyloid angiopathy ("CAA") or
hereditary cerebral
hemorrhage.
In certain embodiments, the therapeutic formulation of the invention is
capable of
inhibiting an interaction between an amyloidogenic protein and a constituent
of a basement
membrane, e.g., a glycoprotein or a proteoglycan, to thus inhibit amyloid
deposition. The
ability of a therapeutic compound of the invention to inhibit an interaction
between an
amyloidogenic protein and a glycoprotein or proteoglycan constituent of a
basement
membrane can be assessed by an in vitro binding assay, such as the mass
spectroscopy assay
described herein (Example 5) or in U.S. Patent No. 5,164,295, which is hereby
expressly
incorporated herein by reference in its entirety.
The present invention relates to a method for inhibiting amyloid deposition in
a
subject comprising administering to the subject an effective amount of a
therapeutic
formulation as described herein, the therapeutic formulation comprising a
therapeutic
compound that comprises at least one sulfonate group covalently attached to a
substituted or
unsubstituted aromatic or aliphatic molecule.
In another embodiment, the invention includes a method for inhibiting the
binding of
a chemokine to a glycosaminoglycan comprising administering a therapeutic
formulation
comprising a therapeutic compound as described herein.
In yet another embodiment, the invention relates to a method for modulating
interaction between a bacterium and a glycosaminoglycan in a human comprising
administering to the human a therapeutic formulation comprising a therapeutic
compound as
described herein. Accordingly, the present invention also pertains to a method
for treating a
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bacterial infection in a human, the method comprising administering to the
human a
therapeutic formulation comprising a therapeutic compound of the invention. In
a specific
embodiment, the invention is a method for treating a subject afflicted with
Chlamydia
comprising administering to the subject a therapeutic formulation comprising a
therapeutic
compound as described herein
In an additional embodiment, the invention includes a method for modulating
interaction between a virus and a glycosaminoglycan in a subject comprising
administering to
the subject a therapeutic formulation comprising a therapeutic compound as
described herein.
More generally, another embodiment of the invention is a method for treating a
viral infection
in a subject comprising administering to the subject a therapeutic formulation
comprising a
therapeutic compound of the invention. In a specific embodiment, the invention
is a method
for treating a subject afflicted with HSV comprising administering to the
subject a therapeutic
formulation comprising a therapeutic compound as described herein.
Additionally, one embodiment of the invention is a method for reducing amyloid
deposits in a subject having amyloid deposits, the method comprising
administering to the
subject an effective amount of a therapeutic formulation comprising a
therapeutic compound
as described herein, such that amyloid deposits are reduced in the subject.
Another embodiment of the invention pertains to a method of preventing,
treating or
inhibiting cerebral amyloid angiopathy in a subject, comprising administering
a therapeutic
formulation comprising a therapeutic compound of the invention to the subject.
Furthermore,
the invention includes a method of preventing, treating, or inhibiting
cerebral amyloid
angiopathy, comprising contacting a blood vessel wall cell with a therapeutic
formulation
comprising a therapeutic compound of the invention, such that cerebral amyloid
angiopathy is
prevented, treated, or inhibited. In addition, the invention includes a method
of preventing,
treating, or inhibiting cerebral amyloid angiopathy, comprising contacting a
blood vessel wall
cell with a therapeutic compound of a therapeutic formulation of the
invention, such that
cerebral amyloid angiopathy is prevented, treated, or inhibited.
The language "inhibition of amyloid deposition" includes reducing, preventing
or
stopping of amyloid formation, e.g., fibrillogenesis, inhibiting or slowing
down of further
amyloid deposition in a subject with amyloidosis, e.g., already having amyloid
deposits, and
reducing or reversing amyloid fibrillogenesis or deposits in a subject with
ongoing
amyloidosis. For example, the extent of the inhibition of amyloid deposition
is contemplated
by the instant application as a range, which can include, for example,
substantially complete
elimination of amyloid deposition or reduction of amyloid deposition.
Inhibition of amyloid
deposition is determined relative to an untreated subject, or relative to the
treated subject
prior to treatment, or, e.g., determined by clinically measurable improvement
in pancreatic
function in a diabetic patient, or in the case of a patient with brain
amyloidosis, e.g., an
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CA 02504471 2005-04-12
Alzheimer's or cerebral amyloid angiopathy patient, stabilization of cognitive
function or
prevention of a further decrease in cognitive function (i.e., preventing,
slowing, or stopping
disease progression), or improvement of parameters such as the concentration
of A(3 or tau in
the CSF. In certain embodiments, amyloid deposition may be inhibited by, for
example,
inhibiting an interaction between an amyloidogenic protein and a constituent
of basement
membrane, enhancing clearance of amyloid (3 from the brain, or inhibiting
neurodegeneration
or cellular toxicity induced by amyloid (e.g., by soluble or insoluble
amyloid, e.g., fibrils, by
amyloid deposition and/or by amyloid-~, as described herein), or protecting
brain cells from
the detrimental effect of A(3.
The language "basement membrane" refers to an extracellular matrix comprising
glycoproteins and proteoglycans, including laminin, collagen type IV,
fibronectin, agrin,
perlecan, and heparan sulfate proteoglycan (HSPG). In one embodiment, amyloid
deposition
is inhibited by interfering with an interaction between an amyloidogenic
protein and a
sulfated glycosaminoglycan such as HSPG. Sulfated glycosaminoglycans are known
to be
present in all types of amyloids (see Snow, A. D., et al. Lab. Invest. 56, 120-
123 (1987)) and
amyloid deposition and HSPG deposition occur coincidentally in animal models
of
amyloidosis (see Snow, A. D., et al., Lab. Invest. 56, 665-675 (1987)).
As used herein, "treatment" of a subject includes the application or
administration of a
composition of the invention to a subject, or application or administration of
a composition of
the invention to a cell or tissue from a subject, who has a amyloid-related
disease or
condition, has a symptom of such a disease or condition, or is at risk of (or
susceptible to)
such a disease or condition, with the purpose of curing, healing, alleviating,
relieving,
altering, remedying, ameliorating, improving, or affecting the disease or
condition, the
symptom of the disease or condition, or the risk of (or susceptibility to) the
disease or
condition. The term "treating" refers to any indicia of success in the
treatment or amelioration
of an injury, pathology or condition, including any objective or subjective
parameter such as
abatement; remission; diminishing of symptoms or making the injury, pathology
or condition
more tolerable to the subject; slowing in the rate of degeneration or decline;
making the final
point of degeneration less debilitating; improving a subject's physical or
mental well-being;
or, in some situations, preventing the onset of dementia. The treatment or
amelioration of
symptoms can be based on objective or subjective parameters; including the
results of a
physical examination, a psychiatric evaluation, or a cognition test such as
Clinical Dementia
Rating (CDR) scale, Mini-mental State Examination (MMSE), Alzheimer's Disease
Assessment Scale-Cognitive Subscale (ADAS-Cog), or another test known in the
art. For
example, the methods of the invention successfully treat a subject's dementia
by slowing the
rate of or lessening the extent of cognitive decline.
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CA 02504471 2005-04-12
In one embodiment, the term "treating" includes maintaining a subject's CDR
rating
at its base line rating or at 0. In another embodiment, the term treating
includes decreasing a
subject's CDR rating by about 0.25 or more, about 0.5 or more, about 1.0 or
more, about 1.5
or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more. In
another embodiment,
the term "treating" also includes reducing the rate of the increase of a
subject's CDR rating as
compared to historical controls. In another embodiment, the term includes
reducing the rate
of increase of a subject's CDR rating by about 5% or more, about 10% or more,
about 20% or
more, about 25% or more, about 30% or more, about 40% or more, about 50% or
more, about
60% or more, about 70% or more, about 80% or more, about 90% or more, or about
100%, of
the increase of the historical or untreated controls.
In another embodiment, the term "treating" also includes maintaining a
subject's score
on the MMSE. The term "treating" includes increasing a subject's MMSE score by
about 1,
about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15,
about 17.5,
about 20, or about 25 points. The term also includes reducing the rate of the
decrease of a
subject's MMSE score as compared to historical controls. In another
embodiment, the term
includes reducing the rate of decrease of a subject's MMSE score may be about
5% or less,
about 10% or less, about 20% or less, about 25% or less, about 30% or less,
about 40% or
less, about 50% or less, about 60% or less, about 70% or less, about 80% or
less, about 90%
or less or about 100% or less, of the decrease of the historical or untreated
controls.
In yet another embodiment, the term "treating" includes maintaining a
subject's score
on the ADAS-Cog. The term "treating" includes decreasing a subject's ADAS-Cog
score by
about 1 point or greater, by about 2 points or greater, by about 3 points or
greater, by about 4
points or greater, by about 5 points or greater, by about 7.5 points or
greater, by about 10
points or greater, by about 12.5 points or greater, by about 15 points or
greater, by about 17.5
points or greater, by about 20 points or greater, or by about 25 points or
greater. The term
also includes reducing the rate of the increase of a subject's ADAS-Cog score
as compared to
historical controls. In another embodiment, the term includes reducing the
rate of increase of
a subject's ADAS-Cog score by about 5% or more, about 10% or more, about 20%
or more,
about 25% or more, about 30% or more, about 40% or more, about 50% or more,
about 60%
or more, about 70% or more, about 80% or more, about 90% or more or about 100%
of the
increase of the historical or untreated controls.
In another embodiment, the term "treating," for example, for AA or AL
amyloidosis,
includes an increase in serum creatinine clearance, e.g., an increase of
creatinine clearance of
10% or greater, 20% or greater, 50% or greater, 80% or greater, 90% or
greater, 100% or
greater, 150% or greater, 200% or greater. The term "treating" also may
include remission of
nephrotic syndrome (NS). It may also include remission of chronic diarrhea
and/or a gain in
body weight, e.g., by 10% or greater, 15% or greater, or 20% or greater.
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The term "prevention" or "preventing" is also used to describe the application
or
administration of a composition of the invention to a subject who is at risk
of (or susceptible
to) such a disease or condition. Patients amenable to treatment for prevention
of the disease
or condition include individuals at risk of the disease or condition but not
showing symptoms,
as well as patients presently showing symptoms. In the case of Alzheimer's
disease, virtually
anyone is at risk of suffering from Alzheimer's disease if he or she lives
long enough.
Therefore, the present methods can be administered prophylactically to the
general population
without any assessment of the risk of the subject patient. But the present
methods are
especially useful for individuals who do have a known risk of Alzheimer's
disease. Such
individuals include those having relatives who have experienced this disease,
and those
whose risk is determined by analysis of genetic or biochemical markers,
including brain
plaques diagnosed by imaging methods, e.g., MRI, PET, SPECT etc.. Examples of
such
imaging methods are discussed in Burggren et al., Current Topics in Medicinal
Chemistry,
vol. 2002, no. 2, pp. 385-393, and Sair et al., Neuroradiology, vol. 46, pp.
93-104 (2002).
Genetic markers of risk toward Alzheimer's disease include mutations in the
APP gene,
particularly mutations at position 717 and positions 670 and 671 referred to
as the Hardy and
Swedish mutations respectively (see Hardy et al., TINS 20, 154-158 (1997)).
Other markers
of risk are mutations in the presenilin genes, PS 1 and PS2, and ApoE4, family
history of AD,
hypercholesterolemia or atherosclerosis. Individuals presently suffering from
Alzheimer's
disease can be recognized from characteristic dementia, as well as the
presence of risk factors
described above. In addition, a number of diagnostic tests based on cognitive
and
neurological testing are available for identifying individuals who have AD.
For example,
individuals suffering from Alzheimer's disease can be diagnosed by the
Clinical Dementia
Rating (CDR) scale, Mini-mental State Examination (MMSE), Alzheimer's Disease
Assessment Scale-Cognitive Subscale (ADAS-Cog), or another test known in the
art, as
discussed herein. Baseline scores on suitable metrics including the MMSE and
the ADAS
together with other metrics designed to evaluate a more normal population can
be used to find
an at risk population. Another method for identifying an at risk group
utilizes an assay for
neural thread protein in the urine; see, e.g., Munzar et al., Neurology and
Clinical
Neurophysiology, Vol. 2002, No. 1. Patients with high risk for Alzheimer's
Disease can also
be selected from a population by screening for early signs of memory loss or
other difficulties
associated with pre-Alzheimer's symptomatology, a family history of
Alzheimer's Disease,
patients with MCI, genetic risk factors, age, sex, and other features found to
predict high-risk
for Alzheimer's Disease.
Without wishing to be bound by theory, in some aspects the pharmaceutical
compositions of the invention contain a compound that prevents or inhibits
amyloid fibril
formation, either in the brain or other organ of interest (acting locally) or
throughout the
entire body (acting systemically). Pharmaceutical compositions of the
invention may be
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effective in controlling amyloid deposition either following their entry into
the brain
(following penetration of the blood brain barrier) or from the periphery. When
acting from
the periphery, a compound of a pharmaceutical composition may alter the
equilibrium of
amyloidogenic peptide between the brain and the plasma to favor the exit of
amyloidogenic
peptide from the brain. It may also favor clearance (or catabolism) of the
amyloid protein
(soluble), and then prevent amyloid fibril formation and deposition due to a
reduction of the
amyloid protein pool in a specific organ, e.g., liver, spleen, pancreas,
kidney, joints, brain, etc.
An increase in the exit of amyloidogenic peptide from the brain would result
in a decrease in
amyloidogenic peptide brain concentration, and therefore, favor a decrease in
amyloidogenic
peptide deposition. In particular, an agent may lower the levels of amyloid ~i
peptides, e.g.,
both A(340 and A(342 in the CSF and the plasma, or the agent may lower the
levels of amyloid
(3 peptides, e.g., A(340 and A(342 in the CSF and increase it in the plasma.
Alternatively,
compounds that penetrate the brain could control deposition by acting directly
on brain
amyloidogenic peptide e.g., by maintaining it in a non-fibrillar form or
favoring its clearance
from the brain, by increasing its degradation in the brain, or protecting
brain cells from the
detrimental effect of amyloidogenic peptide. An agent can also cause a
decrease of the
concentration of the amyloid protein (i.e., in a specific organ so that the
critical concentration
needed to trigger amyloid fibril formation or deposition is not reached).
Furthermore, the
compounds described herein may inhibit or reduce an interaction between
amyloid and a cell
surface constituent, for example, a glycosaminoglycan or proteoglycan
constituent of a
basement membrane. The compounds may also prevent an amyloid peptide from
binding or
adhering to a cell surface, a process that is known to cause cell damage or
toxicity. Similarly,
the compounds may block amyloid-induced cellular toxicity or microglial
activation or
amyloid-induced neurotoxicity, or inhibit amyloid induced inflammation. The
compounds
may also reduce the rate or amount of amyloid aggregation, fibril formation,
or deposition, or
the compounds may lessen the degree of amyloid deposition. The foregoing
mechanisms of
action should not be construed as limiting the scope of the invention inasmuch
as the
invention may be practiced without such information.
The term "significantly," or "significant," is descriptive of the changes in
an identified
property that occur in noticeable or measurable amounts or increments, or
where such
changes would have a noticeable, measurable, or unacceptable impact, e.g., a
detrimental
impact. As such, the language "significantly reduce or prevent
gastrointestinal intolerance"
includes a noticeable or measurable reduction or prevention of
gastrointestinal intolerance,
i.e., as opposed to the situation where the reduction or prevention is not
noticeable or
measurable. For example, the number of incidents of nausea, vomiting, and
gastrointestinal-
associated pain or irntation tracked over time may be used as a measure of the
impact of the
therapeutic formulations of the present invention on the reduction or
prevention of
gastrointestinal intolerance. Additionally, the language "do not significantly
affect the ability
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of the therapeutic formulation" is descriptive of items that affect the
ability of the therapeutic
formulation, but do not affect the ability in an unacceptable manner to the
extent that the cost
outweighs the benefit, and therefore do not "significantly affect" the ability
of the therapeutic
formulation.
"Modulation of amyloid deposition" includes both inhibition, as defined above,
and
enhancement of amyloid deposition or fibril formation. The term "modulating"
is intended,
therefore, to encompass 1 ) prevention or stopping of amyloid formation or
accumulation,
inhibition or slowing down of further amyloid aggregation in a subject with
ongoing
amyloidosis, e.g., already having amyloid aggregates, and reducing or
reversing of amyloid
aggregates in a subject with ongoing amyloidosis, and 2) enhancing amyloid
deposition, e.g.,
increasing the rate or amount of amyloid deposition in vivo or in vitro.
Amyloid-enhancing
compounds may be useful in animal models of amyloidosis, for example, to make
possible
the development of amyloid deposits in animals in a shorter period of time or
to increase
amyloid deposits over a selected period of time. Amyloid-enhancing compounds
may be
useful in screening assays for compounds which inhibit amyloidosis in vivo,
for example, in
animal models, cellular assays and in vitro assays for amyloidosis. Such
compounds may be
used, for example, to provide faster or more sensitive assays for compounds.
Modulation of
amyloid aggregation is determined relative to an untreated subject or relative
to the treated
subject prior to treatment.
The term "therapeutic formulation" includes formulations that perform their
intended
therapeutic function, e.g., prevent, treat or inhibit amyloidosis, and are
used to reduce or
prevent gastrointestinal intolerance (i.e. nausea and vomiting). The reduction
or prevention
of gastrointestinal intolerance may, for example, depend on direct physical
interaction in the
stomach or indirect central action on the Central Nervous System.
In certain embodiments, the reduction or prevention of the gastrointestinal
intolerance
is at least dependent upon the therapeutic compound administered to the
subject. In one
embodiment, the therapeutic compound having a desirable therapeutic function
is selected for
inclusion in the therapeutic formulation based on its ability to reduce or
prevent
gastrointestinal intolerance. In certain embodiments, the compound is modified
in order to
produce a therapeutic compound having a desirable therapeutic function and an
ability to
reduce or prevent gastrointestinal intolerance. For example, the compound may
be
structurally modified (e.g., adding appropriate substituents or altering the
pharmaceutically
acceptable counter ion) or reformulated such that the compound has a desirable
therapeutic
function and an ability to reduce or prevent gastrointestinal intolerance.
In certain other embodiments, the reduction or prevention of the
gastrointestinal
intolerance is not dependent upon the therapeutic compound administered to the
subject
alone. For example, in one embodiment, the reduction or prevention of the
gastrointestinal
-44- Attny Docket - NEURO-3
,. ,
CA 02504471 2005-04-12
intolerance is not dependent upon the therapeutic compound having the formula
3-amino-
1-propanesulfonate / X, where X is a counter cation or forms an ester with the
sulfonate, e.g.,
3-amino-1-propanesulfonic acid, or the sodium salt thereof. In a particular
embodiment of
the invention, the reduction or prevention of the gastrointestinal intolerance
is dependent on
an additional agent, such as enteric-coating or a modified-release agent.
In another embodiment, at least one additional agent is included in the
therapeutic
formulation, where the additional agent differs from the therapeutic compound.
In a specific
embodiment, the additional agent imparts at least one desirable property to
the therapeutic
formulation. In a particular embodiment, the desirable property, at least in
part, reduces or
prevents gastrointestinal intolerance. Accordingly, in an additional
embodiment, an
additional agent may be used in the therapeutic formulation to reduce or
prevent
gastrointestinal intolerance independently or in conjunction with other
methods of reducing or
preventing intolerance. For example, to protect against any possible
gastrointestinal
intolerance that could result from the therapeutic formulation, the tablets
may be enteric-
coated or a modified-release agent may be added to control any rapid release
of the
therapeutic compound in the stomach or intestine.
In one embodiment of the invention, the reduction or prevention of
gastrointestinal
intolerance is accomplished by the reduction or prevention of a local
irritation as a result of
high pH generated during the dissolution of therapeutic compound in the
stomach subsequent
to the administration of the therapeutic compound. As an additional advantage
of the
therapeutic formulations of the present invention, the reduction in
gastrointestinal intolerance
also leads to improved compliance by subjects of administration, e.g.,
patients.
In another particular embodiment, the therapeutic compound of the invention is
an
alkylsulfonic acid. The term "alkylsulfonic acid" includes substituted or
unsubstituted
alkylsulfonic acids, and substituted or unsubstituted lower alkylsulfonic
acids. Amino-
substituted compounds are especially noteworthy and the invention pertains to
substituted- or
unsubstituted-amino-substituted alkylsulfonic acids, and substituted- or
unsubstituted-amino-
substituted lower alkylsulfonic acids, an example of which is 3-amino-1-
propanesulfonic
acid. Also, it should be noted that the term "alkylsulfonic acid" as used
herein is to be
interpreted as being synonymous with the term "alkanesulfonic acid."
In certain embodiments, the invention pertains to a substituted or
unsubstituted
alkylsulfonic acid, substituted or unsubstituted alkylsulfuric acid,
substituted or unsubstituted
alkylthiosulfonic acid, substituted or unsubstituted alkylthiosulfuric acid,
or an ester or amide
thereof, including pharmaceutically acceptable salts thereof. For example, the
invention
relates to a compound that is a substituted or unsubstituted alkylsulfonic
acid, or an ester or
amide thereof, including pharmaceutically acceptable salts thereof. In another
embodiment,
the invention pertains to a compound that is a substituted or unsubstituted
lower alkylsulfonic
-45- Attny Docket - NEURO-3
E. ,
CA 02504471 2005-04-12
acid, or an ester or amide thereof, including pharmaceutically acceptable
salts thereof.
Similarly, the invention includes a compound that is a (substituted- or
unsubstituted-amino)-
substituted alkylsulfonic acid, or an ester or amide thereof, including
pharmaceutically
acceptable salts thereof. In yet another embodiment, the compound is a
(substituted- or
unsubstituted-amino)-substituted lower alkylsulfonic acid, or an ester or
amide thereof,
including pharmaceutically acceptable salts thereof.
Compositions of alkylsulfonic acids, including, for example, 3-amino-
1-propanesulfonic acid and certain salts thereof have been shown to be useful
in the treatment
of amyloid-(3 related diseases, including Alzheimer's disease and cerebral
amyloid
angiopathy. See WO 96/28187, WO 01/85093, and U.S. Patent No. 5,840,294.
One group of example alkylsulfonic acids have the following structure
Y
~S03X
where Y is either an amino group (having the formula -NRaRb wherein Ra and Rb
are each
independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and Rb, taken
together with the
nitrogen atom to which they are attached, form a cyclic moiety having from 3
to 8 atoms in
the ring) or a sulfonic acid group (having the formula -S03 X+), n is an
integer from 1 to 5,
and X is hydrogen or a cationic group (e.g., sodium). Some exemplary
alkylsulfonic acids
include the following
H03S~S03H Na03S~S03Na
H03S~NH2 Na03S~NH2
Alkylsulfonic acids may be prepared by the methods illustrated in the general
reaction
schemes as, for example, described in US 5,643,562; 5,972,328; 5,728,375;
5,840,294;
4,657,704; and the U.S. provisional patent application no. 60/482,058, filed
June 23, 2003,
identified by Attorney Docket No. NBI-156-l, U.S. provisional patent
application no.
60/512,135, filed October 17, 2003, identified by Attorney Docket No. NBI-156-
2, both
entitled Synthetic Process for Preparing Compounds for Treating Amyloidosis,
and U.S.
application 10/871,543, filed June 18, 2004, identified by Attorney Docket No.
NBI-156,
published as WO 2004/11391 and entitled Improved Pharmaceutical Drug
Candidates and
Method for Preparation Thereof, the contents of which are hereby expressly
incorporated by
reference in their entireties, or by modifications thereof, using readily
available starting
materials, reagents and conventional synthesis procedures. In these reactions,
it is also
possible to make use of variants which are in themselves known, but are not
mentioned. For
-46- Attny Docket - NEURO-3
a . .,
CA 02504471 2005-04-12
example, functional and structural equivalents of the compounds described
herein and which
have the same general properties, (wherein one or more simple variations of
substituents are
made that do not adversely affect the essential nature or the utility of the
compound) may be
prepared according to a variety of methods known in the art.
In general, the compounds of the present invention may be prepared by the
methods
illustrated in the general reaction schemes as, for example, described below,
or by
modifications thereof, e.g., using readily available starting materials,
reagents and
conventional synthesis procedures. In these reactions, it is also possible to
make use of
variants which are in themselves known, but are not mentioned here. Functional
and
structural equivalents of the agents described herein and that have the same
general
properties, wherein one or more simple variations of substituents are made
which do not
adversely affect the essential nature or the utility of the compound. The
agents of the present
invention may be readily prepared in accordance with the synthesis schemes and
protocols
described herein, as illustrated in the specific procedures provided. However,
those skilled in
the art will recognize that other synthetic pathways for forming the agents of
this invention
may be used, and that the following is provided merely by way of example, and
is not limiting
to the present invention. See, e.g., "Comprehensive Organic Transformations"
by R. Larock,
VCH Publishers (1989). It will be further recognized that various protecting
and deprotecting
strategies will be employed that are standard in the art (See, e.g.,
"Protective Groups in
Organic Synthesis" by Greene and Wuts). Those skilled in the relevant arts
will recognize
that the selection of any particular protecting group (e.g., amine and
carboxyl protecting
groups) will depend on the stability of the protected moiety with regards to
the subsequent
reaction conditions and will understand the appropriate selections. Further
illustrating the
knowledge of those skilled in the art is the following sampling of the
extensive chemical
literature: "Chemistry of the Amino Acids" by J.P. Greenstein and M. Winitz,
John Wiley &
Sons, Inc., New York (1961); "Comprehensive Organic Transformations" by R.
Larock, VCH
Publishers (1989); T.D. Ocain, et al., J. Med. Chem. 31, 2193-99 (1988); E.M.
Gordon, et al.,
J. Med. Chem. 31, 2199-10 (1988); "Practice of Peptide Synthesis" by M.
Bodansky and
A. Bodanszky, Springer-Verlag, New York (1984); "Protective Groups in Organic
Synthesis"
by T. Greene and P. Wuts (1991); "Asymmetric Synthesis: Construction of Chiral
Molecules
Using Amino Acids" by G.M. Coppola and H.F. Schuster, John Wiley & Sons, Inc.,
New
York (1987); "The Chemical Synthesis of Peptides" by J. Jones, Oxford
University Press,
New York (1991); and "Introduction of Peptide Chemistry" by P.D. Bailey, John
Wiley &
Sons, Inc., New York (1992).
The chemical structures herein are drawn according to the conventional
standards
known in the art. Thus, where an atom, such as a carbon atom, as drawn appears
to have an
unsatisfied valency, then that valency is assumed to be satisfied by a
hydrogen atom even
though that hydrogen atom is not necessarily explicitly drawn. The structures
of some of the
-47- Attny Docket - NEURO-3
.. . r... .
CA 02504471 2005-04-12
compounds of this invention include stereogenic carbon atoms. It is to be
understood that
isomers arising from such asymmetry (e.g., all enantiomers and diastereomers)
are included
within the scope of this invention unless indicated otherwise. That is, unless
otherwise
stipulated, any chiral carbon center may be of either (R)- or (S~-
stereochemistry. Such
isomers can be obtained in substantially pure form by classical separation
techniques and by
stereochemically-controlled synthesis. Furthermore, alkenes can include either
the E- or Z-
geometry, where appropriate. In addition, the compounds of the present
invention may exist
in unsolvated as well as solvated forms with acceptable solvents such as
water, THF, ethanol,
and the like, as well as polymorphic forms, e.g., including pseudopolymorphic
forms. The
term "solvate" represents an aggregate that comprises one or more molecules of
a compound,
with one or more molecules of a pharmaceutical solvent, such as water,
ethanol, and the like.
Further examples of compounds that may be used as a compound according to the
present invention include those described in the U.S. provisional patent
application no.
60/480,906, filed June 23, 2003, identified by Attorney Docket No. NBI-162-1,
and U.S.
provisional patent application no. 60/512,047, filed October 17, 2003,
identified by Attorney
Docket No. NBI-162-2, U.S. application 10/871,514 (W02004/113275), filed June
18, 2004,
identified by Attorney Docket No. NBI-162A and U.S. application 10/871,365 (WO
2005/0038117), filed June 18, 2004, identified by Attorney Docket No. NCI-162B
(formerly
NBI-162B), all entitled Methods and Compositions for Treating Amyloid-Related
Diseases;
and U.S. provisional patent application no. 60/480,928, also filed 23 June
2003, identified by
Attorney Docket No. NBI-163-1, U.S. provisional patent application no.
60/512,018, filed
October 17, 2003, identified by Attorney Docket No. NBI-163-2 and U.S.
application
10/871,512 (WO 2005/0038000), filed June 18, 2004, identified by Attorney
Docket No.
NBI-163, all entitled Methods and Compositions for the Treatment of Amyloid-
and
Epileptogenesis-Associated Diseases.
In an embodiment, the invention pertains, at least in part to a composition
having a
therapeutic compound that is a compound of Formula I-A:
R2
Ri\ I Y
\L1/ ~Lz/ . (I_A)
wherein:
R' is a substituted or unsubstituted cycloalkyl, aryl, arylcycloalkyl,
bicyclic or tricyclic
ring, a bicyclic or tricyclic fused ring group, or a substituted or
unsubstituted CZ-Clo alkyl
group;
RZ is selected from the group consisting of hydrogen, alkyl, mercaptoalkyl,
alkenyl,
-48- Attny Docket - NEURO-3
,.. . ~.._ . . .. .,".
CA 02504471 2005-04-12
alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, and
benzoimidazolyl;
Y is S03~+, OS03~+, or SS03-X+;
X+ is hydrogen, a cationic group, or an ester forming group (i.e., as in a
prodrug,); and
each of Ll and L2 is independently a substituted or unsubstituted C1-CS alkyl
group or
absent, or a pharmaceutically acceptable salt thereof, provided that when Rl
is alkyl, Ll is
absent.
In another embodiment, the invention pertains, at least in part to a
composition having
a therapeutic compound that is a compound of Formula II-A:
R2 O
I II
R~-L, N-~C)m-~Cf"~2)~
(B-A)
wherein:
Rl is a substituted or unsubstituted cyclic, bicyclic, tricyclic, or
benzoheterocyclic
group or a substituted or unsubstituted C2-Clo alkyl group;
RZ is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl,
thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or linked
to Rl to form a
heterocycle;
Y is S03-X+, OS03-X+, or SS03-X+;
X+ is hydrogen, a cationic group, or an ester forming moiety;
m is 0 or l;
n is 1, 2, 3, or 4;
L is substituted or unsubstituted Cl-C3 alkyl group or absent,
or a pharmaceutically acceptable salt thereof, provided that when Rl is alkyl,
L is absent. In a
particular embodiment, n is 3 or 4.
In yet another embodiment, the invention pertains, at least in part to a
composition
having a therapeutic compound that is a compound of Formula III-A:
Raa Rs
R4 Rsa
O
\N-(CH2)~ S-A-Ri ~
R~ Rs O
Rya Rsa
wherein:
A is nitrogen or oxygen;
-49- Attny Docket - NEURO-3
.4 ... ... ., ..,," . _..
CA 02504471 2005-04-12
R' 1 is hydrogen, salt-forming cation, ester forming group, -(CH2)X-Q, or when
A is
nitrogen, A and Rl1 taken together may be a natural or unnatural amino acid
residue or a salt
or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
x is 0, 1, 2, 3, or 4;
n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
Rs~ R3a~ Ra~ Raa~ Rs~ Rsa~ R6~ R6a~ R7 and R7a are each independently
hydrogen, alkyl,
mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl,
arylcarbonyl; alkoxycarbonyl,
cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms
taken together with
the ring atoms form a double bond. In a particular embodiment, n is 3 or 4. In
certain
embodiments, one of R3, R3a, R4, R4a, Rs, Rsa, R6, R6a, R7 and R~a is a moiety
of Formula IIIa-
A:
RA
RB ~ _(CH~.
RC' Y ~ RE
wherein:
m is 0, 1, 2, 3, or 4;
RA, RB, R~, RD, and RE are independently selected from a group of hydrogen,
halogen,
hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl,
cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and
benzoimidazolyl; and
pharmaceutically acceptable salts and esters thereof. In certain embodiments,
said compound
is not 3-(4-phenyl-1, 2, 3, 6-tetrahydro-1-pyridyl)-1-propanesulfonic acid.
An ester forming group or moiety includes groups, which when bound, form an
ester.
Examples of such groups include substituted or unsubstituted alkyl, aryl,
alkenyl, alkynyl, or
cycloalkyl. Particular examples of possible esters include methyl, ethyl, and
t-butyl.
Additionally, examples of salt forming cations include pharmaceutically
acceptable salts
described herein as well as lithium, sodium, potassium, magnesium, calcium,
barium, zinc,
iron, and ammonium. In a further embodiment, the salt forming cation is a
sodium salt.
In yet another embodiment, the invention pertains at least in part to a
composition
having a therapeutic compound that is a compound of Formula IV:
-50- Attny Docket - NEURO-3
CA 02504471 2005-04-12
Rs Rs Ra Raa RsRsa
O
~o ~ H ~~-A_R»
R ~ ~ (CH2)m-N N-(C 2)n-S
R~ ~-~. Rsa O
Rii R~2 Rya Rs
(N-A)
wherein:
A is nitrogen or oxygen;
R' 1 is hydrogen, salt-forming cadon, ester forming group, -(CH2)X-Q, or when
A is
nitrogen, A and Rl1 taken together may be a natural or unnatural amino acid
residue or a salt
or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
xis0,1,2,3,or4;
n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
R4, R4a, R5, Rsa, R6, Rte, R7, and R7a are each independently hydrogen, alkyl,
mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl,
cyano, halogen, amino, tetrazolyl, R4 and RS taken together, with the ring
atoms they are
attached to, form a double bond, or R6 and R? taken together, with the ring
atoms they are
attached to, form a double bond;
m is 0, 1, 2, 3, or 4;
R8, R9, R'°, R11, and R12 are independently selected from a group of
hydrogen,
halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl,
alkynyl,
cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl,
benzothiazolyl, and
benzoimidazolyl, and pharmaceutically acceptable salts and esters thereof. In
a particular
embodiment, n is 3 or 4.
In another embodiment, the invention includes a composition having a
therapeutic
compound that is a compound of Formula V-A:
R'S O
R~ a-(aa)m ~ -(CH2)n-I I A R1 ~
O (V-A)
wherein:
A is nitrogen or oxygen;
Rl1 is hydrogen, salt-forming cation, ester forming group, -(CHz)X~, or when A
is
nitrogen, A and R' 1 taken together may be a natural or unnatural amino acid
residue or a salt
or ester thereof;
-51- Attny Docket - NEURO-3
CA 02504471 2005-04-12
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
xis0, 1,2,3,or4;
n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
as is a natural or unnatural amino acid residue;
mis0,1,2,or3;
R'4 is hydrogen or protecting group;
R'S is hydrogen, alkyl or aryl, and pharmaceutically acceptable salts and
prodrugs
thereof. In a particular embodiment, n is 3 or 4.
In another embodiment, the invention includes a composition having a
therapeutic
compound that is a compound of the Formula VI-A:
R22
O
Rz~
jY2-~~-N-~~H~~ ~~-A-Rtt
R2o
(VI-A)
wherein:
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
A is oxygen or nitrogen;
Rl ~ is hydrogen, salt-forming cation, ester forming group, -(CHZ)X-Q, or when
A is
nitrogen, A and Rl l taken together may be a natural or unnatural amino acid
residue or a salt
or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
x is 0, 1, 2, 3, or 4;
R19 is hydrogen, alkyl or aryl;
Yl is oxygen, sulfur, or nitrogen;
YZ is carbon, nitrogen, or oxygen;
RZ° is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl,
arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
R21 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl,
thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl,
or absent if Y2 is
oxygen;
RZZ is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl,
thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl;
or R22 is
hydrogen, hydroxyl, alkoxy or aryloxy if Yl is nitrogen; or Rz2 is absent if
Yl is oxygen or
sulfur; or R22 and R21 may be linked to form a cyclic moiety if Yl is
nitrogen;
or pharmaceutically acceptable salts thereof. In a particular embodiment, n is
3 or 4.
-52- Attny Docket - NEURO-3
CA 02504471 2005-04-12
In another embodiment, the invention includes a composition having a
therapeutic
compound that is a compound of Formula VII-A:
0
(CH2)m-N-(CH2)~ ~~-A-R~~
(RzsG) ~ xa ~R-A)
wherein:
n is 2, 3, or 4;
A is oxygen or nitrogen;
Rl1 is hydrogen, salt-forming cation, ester forming group, -(CH2)X-Q, or when
A is
nitrogen, A and R' 1 taken together may be a natural or unnatural amino acid
residue or a salt
or ester thereof;
Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or
benzoimidazolyl;
x is 0, 1, 2, 3, or 4;
G is a direct bond or oxygen, nitrogen, or sulfur;
z is 0, l, 2, 3, 4, .or 5;
mis0or 1;
Rz4 is selected from the group consisting of hydrogen, alkyl, mercaptoalkyl,
alkenyl,
alkynyl, amyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl, arylalkyl,
thiazolyl,
triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;
each R25 is independently selected from hydrogen, halogen, cyano, hydroxyl,
alkoxy,
thiol, amino, nitro, alkyl, aryl, carbocyclic, or heterocyclic, and
pharmaceutically acceptable
salts thereof. In a particular embodiment, n is 3 or 4.
Additional compounds include, for example, therapeutic compounds of Formula (I-
B):
NHR2
3 _ 1
R m n ZiX R (I_B)
wherein:
X is oxygen or nitrogen;
Z is C=O, S(O)2, or P(O)OR';
m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R' and R' are each independently hydrogen, metal ion, alkyl, mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, aryl, a moiety together with X to form a natural
or
unnatural amino acid residue, or -(CH2)P Y;
-53- Attny Docket - NEURO-3
CA 02504471 2005-04-12
Y is hydrogen or a heterocyclic moiety selected from the group consisting of
thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, and
benzoimidazolyl;
p is 0, 1, 2, 3, or 4;
Rz is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;
R3 is hydrogen, amino, cyano, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclic, sunbstituted or unsubstituted aryl, heteroaryl,
thiazolyl,
triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl, and
pharmaceutically acceptable salts, esters, and prodrugs thereof.
In a further embodiment, m is 0, 1, or 2. In another further embodiment, n is
0, 1, or 2, e.g., 1 or 2. In another further embodiment, R3 is aryl, e.g.,
heteroaryl or
phenyl. In yet another embodiment, Z is S(O)z.
In another embodiment, the therapeutic compound of the invention is of the
Formula (II-B)
~Rz
(RaJ)q / ~X-Ri
m n ~S~
O O
(II-B)
wherein:
X is oxygen or nitrogen;
m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R' is hydrogen, metal ion, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
aryl, or a moiety together with X to form a natural or unnatural amino acid
residue, or
-(CHz)P Y;
Y is hydrogen or a heterocyclic moiety selected from the group consisting of
thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, and
benzoimidazolyl;
each R4 is independently selected from the group consisting of hydrogen,
halogen, hydroxyl, thiol, amino, cyano, nitro, alkyl, aryl, carbocyclic or
heterocyclic;
Rz is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;
J is absent, oxygen, nitrogen, sulfur, or a divalent link-moiety consisting
of,
without limitation to, lower alkylene, alkylenyloxy, alkylenylamino,
alkylenylthio,
-54- Attny Docket - NEURO-3
CA 02504471 2005-04-12
alkylenyloxyalkyl, alkylenylamonialkyl, alkylenylthioalkyl, alkenyl,
alkenyloxy,
alkenylamino, or alkenylthio; and
q is 1, 2, 3, 4, or 5, and pharmaceutically acceptable salts, esters and
prodrugs
thereof. In a particular embodiment, n is 1 or 2.
In a yet further embodiment, the therapeutic compound of the invention is of
the Formula (III-B):
(Rs~q ~ NHRZ
J / ~X-Rl
m n OSO
(~-B )
wherein:
X is oxygen or nitrogen;
m and n are each independently 0, 1, 2, 3, 4, S, 6, 7, 8, 9 or 10;
qis 1,2,3,4,or5;
R' is hydrogen, metal ion, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
aryl, or a moiety together with X to form a natural or unnatural amino acid
residue, or
-(CHZ)P Y;
Y is hydrogen or a heterocyclic moiety selected from the group consisting of
thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, and
benzoimidazolyl;
p is 0, 1, 2, 3, or 4;
R2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;
RS is selected from the group consisting of hydrogen, halogen, amino, nitro,
hydroxy, carbonyl, thiol, carboxy, alkyl, alkoxy, alkoxycarbonyl, acyl,
alkylamino,
and acylamino;
J is absent, oxygen, nitrogen, sulfur, or a divalent link-moiety consisting
of,
without limitation to, lower alkylene, alkylenyloxy, alkylenylamino,
alkylenylthio,
alkylenyloxyalkyl, alkylenylamonialkyl, alkylenylthioalkyl, alkenyl,
alkenyloxy,
alkenylamino, or alkenylthio; and
pharmaceutically acceptable salts, esters, and prodrugs thereof. In a
particular
embodiment, n is 1 or 2.
In yet another embodiment, the therapeutic compound of the invention is:
-55- Attny Docket - NEURO-3
CA 02504471 2005-04-12
~5)9
NHR2
X-Rl
i
O ~ m n ~S~
O O
(IV-B).
wherein:
X is oxygen or nitrogen;
m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
qis 1,2,3,4,or5;
Rl is hydrogen, metal ion, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
aryl, or a moiety together with X to form a natural or unnatural amino acid
residue, or
~CH2)P Y
Y is hydrogen or a heterocyclic moiety selected from the group consisting of
thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, and
benzoimidazolyl;
p is 0, 1, 2, 3, or 4;
R2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;
RS is selected from the group consisting of hydrogen, halogen, amino, nitro,
hydroxy, carbonyl, thiol, carboxy, alkyl, alkoxy, alkoxycarbonyl, acyl,
alkylamino,
acylamino; and
pharmaceutically acceptable salts, esters, and prodrugs thereof. In a further
embodiment, m is 0. In a particular embodiment, n is 1 or 2.
In another embodiment, the invention pertains to therapeutic compounds of
Formula (V-B):
NHR2
R6 ~X-Ri
m n Z (V_B)
wherein:
X is oxygen or nitrogen,
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Z is C=O, S(O)z, or P(O)OR7;
RI is hydrogen, metal ion, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl,
aryl, or a moiety together with X to form a natural or unnatural amino acid
residue, or
-(CHz)p Y;
Y is hydrogen or a heterocyclic moiety selected from the group consisting of
thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, and
benzoimidazolyl;
m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
Rz is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl; and
R6 is a substituted or unsubstituted heterocyclic moiety. In a further
embodiment, m is 0 or 1. In another embodiment, n is 0 or 1. In another
further
embodiment, R6 is thiazolyl, oxazoylyl, pyrazolyl, indolyl, pyridinyl,
thiazinyl,
thiophenyl, benzothiophenyl, dihydroimidazolyl, dihydrothiazolyl,
oxazolidinyl,
thiazolidinyl, tetrahydropyrimidinyl, or oxazinyl. In yet another embodiment,
Z is
S(O)z. In a particular embodiment, n is 1 or 2.
In certain embodiments of the invention, the therapeutic formulations of the
invention
may contain pharmaceutically acceptable inactive ingredients and a therapeutic
compound
having the formula 3-amino-1-propanesulfonate / X, where X is a counter cation
or forms an
ester with the sulfonate, wherein the ester or counter cation includes alcohol
radicals or
positively charged atoms and moieties, respectively, that do not significantly
affect the ability
of the therapeutic formulation to reduce or prevent gastrointestinal
intolerance. In a preferred
embodiment, the cationic group is hydrogen (H+) and the compound is 3-amino-
1-propanesulfonic acid. In certain other embodiments, the hydrogen is replaced
by a
pharmaceutically acceptable cation or an alcohol radical or its equivalent,
and the compound
is a salt or ester of the acid. Pharmaceutically acceptable salts or esters of
the therapeutic
compound that do not significantly affect the ability of the therapeutic
formulation to reduce
or prevent gastrointestinal intolerance are within the scope of the invention.
For example, the
cation can be a pharmaceutically acceptable alkali metal, alkaline earth,
higher valency cation
(e.g., aluminum salt), polycationic counter ion or ammonium, and the alcohol
radical can be a
pharmaceutically acceptable alcohol radical. In a particular embodiment, the
pharmaceutically acceptable salt is a sodium salt, however, other salts are
also contemplated
within their pharmaceutically acceptable range.
In general, the therapeutic compounds appropriate for use in the therapeutic
formulations of the invention comprise at least one sulfonate group covalently
bonded to a
substituted or unsubstituted aromatic or aliphatic group.
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In another embodiment, the therapeutic compound has at least one sulfonate
group
covalently bonded to a substituted or unsubstituted aliphatic group. In a
similar embodiment
the therapeutic compound has at least two sulfonate groups covalently bonded
to a substituted
or unsubstituted aliphatic group. In another embodiment, the therapeutic
compound has at
least one sulfonate group covalently bonded to a substituted or unsubstituted
lower alkyl
group. In a similar embodiment the therapeutic compound has at least two
sulfonate groups
covalently bonded to a substituted or unsubstituted lower alkyl group.
In yet another embodiment, the therapeutic compound has at least one sulfonate
group
covalently bonded to an amino-substituted aliphatic group. In a similar
embodiment the
therapeutic compound has at least two sulfonate groups covalently bonded to an
amino-
substituted aliphatic group. In still yet another embodiment, the therapeutic
compound has at
least one sulfonate group covalently bonded to an amino-substituted lower
alkyl group. In a
similar embodiment the therapeutic compound has at least two sulfonate groups
covalently
bonded to an amino-substituted lower alkyl group.
A "sulfonate group" as used herein is an -S03-H or -S03X group bonded to a
carbon
atom, where X is a cationic group or an ester group. Similarly, a "sulfonic
acid" compound
has a -S03H group bonded to a carbon atom. A "sulfate" as used herein is an -
OS03 H
or -OS03X group bonded to a carbon atom, where X is a cationic group or an
ester group; and
a "sulfuric acid" compound has a -OS03H group bonded to a carbon atom.
According to the
invention, a suitable cationic group may be a hydrogen atom. In certain cases,
the cationic
group may actually be another group on the therapeutic compound that is
positively charged
at physiological pH, for example an amino group. Such compounds containing
such a
cationic group covalently bonded to the therapeutic compound itself may be
referred to as an
"inner salt" or "zwitterion." For example, the compound 3-amino-1-
propanesulfonic acid
may form an inner salt or zwitterion under appropriate conditions.
Unless otherwise stipulated, the chemical moieties herein may be substituted
or
unsubstituted. In some embodiments, the term "substituted" means that the
moiety has
substituents placed on the moiety other than hydrogen which allow the molecule
to perform
its intended function. Examples of substituents, which are not intended to be
limiting,
include moieties selected from straight or branched alkyl (preferably C1-CS),
cycloalkyl
(preferably C3-C8), alkoxy (preferably CrC6), thioalkyl (preferably Cl-C6),
alkenyl
(preferably Cz-C6), alkynyl (preferably C2-C6), heterocyclic, carbocyclic,
aryl (e.g., phenyl),
aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g.,
phenyloxyalkyl),
arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or
other such acyl
group, heteroarylcarbonyl, or heteroaryl group, (CR'R")o_3NR'R" (e.g., -NH2),
(CR'R")o_3CN
(e.g., -CN), -NOZ, halogen (e.g., -F, -Cl, -Br, or -1], (CR'R")~3C(halogen)3
(e.g., -CF3),
(CR'R")o_3CH(halogen)2, (CR'R")o_3CH2(halogen), (CR'R")o_3CONR'R",
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(CR'R")o-s(C~~'R,~~ (CR,R»)a-3S(O)i-a~'R"~ (CR'R")o-sCHO,
(CR'R")o_30(CR'R")o_3H, (CR'R")o_3S(O)0.3R' (e.g., -S03H, -OS03H),
(CR'R")0.30(CR'R")o-3H (e.g., -CH20CH3 and -OCH3), (CR'R")0.3S(CR'R")~3H
(e.g., -SH
and -SCH3), (CR'R")o_30H (e.g., -OH), (CR'R")a3COR', (CR'R")o_3(substituted or
unsubstituted phenyl), (CR'R")0.3(C3-C8 cycloalkyl), (CR'R")0.3C02R' (e.g., -
C02H), or
(CR'R")~30R' group, or the side chain of any naturally occurring amino acid;
wherein R' and
R" are each independently hydrogen, a C~-CS alkyl, CZ-CS alkenyl, CZ-CS
alkynyl, or aryl
group. "Substituents" may also include, for example, halogen, hydroxyl,
alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,
alkylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato,
phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino,
diarylamino, and
alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl
and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate,
sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, heterocyclyl, aralkyl,
or an aromatic or
heteroaromatic moiety.
It will be understood that "substitution" or "substituted with" includes the
implicit
proviso that such substitution is in accordance with permitted valence of the
substituted atom
and the substituent, and that the substitution results in a stable compound,
e.g., which does
not spontaneously undergo transformation such as by rearrangement,
cyclization, elimination,
etc. As used herein, the term "substituted" includes all permissible
substituents of organic
compounds. In a broad aspect, the permissible substituents include acyclic and
cyclic,
branched and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic
substituents of organic compounds. The permissible substituents can be one or
more and the
same or different for appropriate organic compounds.
In certain embodiments, a "substituent" may be selected from the group
consisting of,
for example, halogeno, trifluoromethyl, nitro, cyano, C~-C6 alkyl, C2-C6
alkenyl,
C2-C6 alkynyl, C,-C6 alkylcarbonyloxy, arylcarbonyloxy, Cl-C6
alkoxycarbonyloxy,
aryloxycarbonyloxy, C~-C6 alkylcarbonyl, C~-C6 alkoxycarbonyl, C1-C6 alkoxy,
C~-C6 alkylthio, arylthio, heterocyclyl, aralkyl, and aryl (including
heteroaryl) groups.
In general, the therapeutic compounds of the invention are small molecules. A
"small
molecule" refers to a compound that is not itself the product of gene
transcription or
translation (e.g., protein, RNA, or DNA). Preferably a "small molecule" is a
low molecular
weight compound, e.g., less than 7500 amu, more preferably less 5000 amu,
e.g., less than
about 2500 amu, and even more preferably less than 1000 amu. In other cases,
the compound
may be a biological product, such as an antibody or an immunogenic peptide.
The term "amine" or "amino," as used herein, refers to an unsubstituted or
substituted
moiety of the formula -NRaRb, in which Ra and Rb are each independently
hydrogen, alkyl,
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aryl, or heterocyclyl, or Ra and Rb, taken together with the nitrogen atom to
which they are
attached, form a cyclic moiety having from 3 to 8 atoms in the ring. Thus, the
tertri amino
includes cyclic amino moieties such as piperidinyl or pyrrolidinyl groups,
unless otherwise
stated. Thus, the term "alkylamino" as used herein means an alkyl group having
an amino
group attached thereto. Suitable alkylamino groups include groups having 1 to
about 12
carbon atoms, for example, 1 to about 6 carbon atoms. The term amino includes
compounds
or moieties in which a nitrogen atom is covalently bonded to at least one
carbon or
heteroatom. The term "dialkylamino" includes groups wherein the nitrogen atom
is bound to
at least two alkyl groups. The term "arylamino" and "diarylamino" include
groups wherein
the nitrogen is bound to at least one or two aryl groups, respectively. The
term
"alkylarylamino" refers to an amino group which is bound to at least one alkyl
group and at
least one aryl group. The term "alkaminoalkyl" refers to an alkyl, alkenyl, or
alkynyl group
substituted with an alkylamino group. The term "amide" or "aminocarbonyl"
includes
compounds or moieties which contain a nitrogen atom which is bound to the
carbon of a
carbonyl or a thiocarbonyl group.
The term "aliphatic group" includes organic compounds characterized by
straight or
branched chains, typically having between 1 and 22 carbon atoms. Aliphatic
groups include
alkyl groups, alkenyl groups and alkynyl groups. The chains may be branched or
cross-
linked. Alkyl groups include saturated hydrocarbons having one or more carbon
atoms,
including straight-chain alkyl groups and branched-chain alkyl groups. The
term "alicyclic
group" includes closed ring structures of three or more carbon atoms.
Alicyclic groups
include cycloparaffins or naphthenes that are saturated cyclic hydrocarbons,
cycloolefins
which are unsaturated with two or more double bonds, and cycloacetylenes which
have a
triple bond. They do not include aromatic groups. Examples of cycloparaffins
include
cyclopropane, cyclohexane, and cyclopentane. Examples of cycloolefins include
cyclopentadiene and cyclooctatetraene. Alicyclic groups also include
polycyclic rings, e.g.,
fused ring structures, and substituted alicyclic groups such as alkyl
substituted alicyclic
groups. "Polycyclyl" or "polycyclic group" includes two or more cyclic rings
(e.g.,
cycloalkyls, cycloalkenyls, cycloalkynyls, aryls or heterocyclyls) in which
one or more
carbons are common to two adjoining rings, e.g., the rings are "fused rings"
or spiro-rings.
Rings that are joined through non-adjacent atoms are termed "bridged" rings.
As used herein, "alkyl" groups include saturated hydrocarbons having one or
more
carbon atoms, including straight-chain alkyl groups, e.g., methyl, ethyl,
propyl, butyl, pentyl,
hexyl, heptyl, octyl, nonyl, decyl, etc.; cyclic alkyl groups (or "cycloalkyl"
or "alicyclic" or
"carbocyclic" groups), e.g., cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl,
etc.; branched-chain alkyl groups, e.g., isopropyl, tent-butyl, sec-butyl,
isobutyl, etc.; and
alkyl-substituted alkyl groups, e.g., alkyl-substituted cycloalkyl groups and
cycloalkyl-substituted alkyl groups.
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Accordingly, the invention relates to, for example, substituted or
unsubstituted
alkylsulfonic acids that are substituted or unsubstituted straight-chain
alkylsulfonic acids,
substituted or unsubstituted cycloalkylsulfonic acids, and substituted or
unsubstituted
branched-chain alkylsulfonic acids.
In certain embodiments, a straight-chain or branched-chain alkyl group may
have 30
or fewer carbon atoms in its backbone, e.g., Cl-C3o for straight-chain or C3-
C3p for
branched-chain. In certain embodiments, a straight-chain or branched-chain
alkyl group may
have 20 or fewer carbon atoms in its backbone, e.g., Cl-Czo for straight-chain
or C3-CZO for
branched-chain, and more particularly, for example, 18 or fewer. Additionally,
example
cycloalkyl groups have from 4-10 carbon atoms in their ring structure, e.g., 4-
7 carbon atoms
in the ring structure.
The term "lower alkyl" refers to alkyl groups having from 1 to 8 carbons in
the chain,
and to cycloalkyl groups having from 3 to 8 carbons in the ring structure.
Unless the number
of carbons is otherwise specified, "lower" as in "lower alkyl," means that the
moiety has at
least one and less than about 8 carbon atoms. In certain embodiments, a
straight-chain or
branched-chain lower alkyl group has 6 or fewer carbon atoms in its backbone
(e.g., Cl-C6 for
straight-chain, C3-C6 for branched-chain),for example, methyl, ethyl, propyl,
isopropyl, butyl,
isobutyl, sec-butyl, and tent-butyl. Likewise, cycloalkyl groups may have from
3-8 carbon
atoms in their ring structure, for example, 5 or 6 carbons in the ring
structure. The term
"C1-C6" as in "Cl-C6 alkyl" means alkyl groups containing 1 to 6 carbon atoms.
Moreover, unless otherwise specified the term alkyl includes both
"unsubstituted
alkyls" and "substituted alkyls," the latter of which refers to alkyl groups
having substituents
replacing one or more hydrogens on one or more carbons of the hydrocarbon
backbone. Such
substituents may include, for example, alkenyl, alkynyl, halogeno, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,
phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and
alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl
and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, alkylsulfinyl,
sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl,
alkylaryl, or aromatic (including heteroaromatic) groups.
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups
analogous to
alkyls, including straight and branched chains, and cyclical structures, but
which contain at
least one double or triple bond respectively. Suitable alkenyl and alkynyl
groups include
groups having 2 to about 12 carbon atoms, preferably from 2 to about 6 carbon
atoms.
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The term "aromatic group" includes unsaturated cyclic hydrocarbons containing
one
or more rings. In general, the term "aryl" includes groups, including 5- and 6-
membered
singl~ring aromatic groups that may include from zero to four heteroatoms, for
example,
groups derived from benzene, pyrrole, furan, thiophene, thiazole,
isothiaozole, imidazole,
triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine,
pyridazine, and
pyrimidine, and the like. Furthermore, the term aryl includes multicyclic aryl
groups, e.g.,
groups derived from tricyclic, bicyclic, e.g., naphthalene, benzoxazole,
benzodioxazole,
benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl,
quinoline,
isoquinoline, napthyridine, indole, benzofuran, purine, benzofuran,
deazapurine, or
indolizine. Those aryl groups having heteroatoms in the ring structure may
also be referred to
as "aryl heterocycles," "heteroaryls," or "heteroaromatics".
Aryl groups may also be fused or bridged with alicyclic or heterocyclic rings
which
are not aromatic so as to form a polycycle (e.g., tetralin). Those aryl groups
having
heteroatoms in the ring structure may also be referred to as aryl
heterocycles, heterocycles,
heteroaryls, or heteroaromatics, which, for example, include any ring formed
that incorporates
a heteroatom or an atom that is not carbon. The ring may be saturated or
unsaturated and may
contain one or more double bonds. Examples of some heterocyclic groups include
pyridyl,
furanyl, thiophenyl, morpholinyl, and indolyl groups.
The term "heteroatom" includes atoms of any element other than carbon or
hydrogen.
Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
Heterocyclic groups also
include closed ring structures in which one or more of the atoms in the ring
is an element
other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic
groups may be
saturated or unsaturated and heterocyclic groups such as pyrrole and furan may
have aromatic
character. They include fused ring structures such as quinoline and
isoquinoline. Other
examples of heterocyclic groups include pyridine and purine. Examples of
heteroaromatic
and heteroalicyclic groups may have 1 to 3 separate or fused rings with 3 to
about 8 members
per ring and one or more N, O, or S atoms, e.g., coumarinyl, quinolinyl,
pyridyl, pyrazinyl,
pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl,
benzofuranyl,
benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino,
and
pyrrolidinyl.
111. Therapeutic Formulations of the Invention
The invention also relates to a pharmaceutical composition for inhibiting
amyloid
deposition in a subject comprising a therapeutic formulation as defined
herein, in an amount
sufficient to inhibit amyloid deposition in a subject, and a pharmaceutically
acceptable
vehicle.
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In another embodiment, the invention is a pharmaceutical composition for
treating
amyloidosis in a subject comprising a therapeutic formulation as described
herein, in an
amount sufficient to inhibit amyloid deposition in a subject, and a
pharmaceutically
acceptable vehicle.
In another embodiment, the present invention pertains to a pharmaceutical
composition for treating or preventing an amyloid-related disease, e.g., type
II diabetes or an
A~-related disease, e.g., Alzheimer's disease, cerebral amyloid angiopathy,
inclusion body
myositis, macular degeneration, Down's syndrome, and hereditary cerebral
hemorrhage,
comprising a therapeutic formulation comprising a therapeutic compound
formulated to
significantly reduce or prevent gastrointestinal intolerance, in an amount
sufficient to prevent
or treat an amyloid-related disease in a subject, and a pharmaceutically
acceptable vehicle.
In certain embodiments, the therapeutic compound of the therapeutic
formulations of
the invention interacts with a binding site for a basement membrane
glycoprotein or
proteoglycan in an amyloidogenic protein and thereby inhibits the binding of
the
amyloidogenic protein to the basement membrane constituent. Basement membrane
glycoproteins and proteoglycans include laminin, collagen type IV,
fibronectin, agrin,
perlecan, and heparan sulfate proteoglycan (HSPG). In a particular embodiment,
the
therapeutic compound inhibits an interaction between an amyloidogenic protein
and agrin,
perlecan, or HSPG. Furthermore, consensus binding site motifs for HSPG in
amyloidogenic
proteins have been described (see e.g. Cardin and Weintraub (1989)
Arteriosclerosis
9:21-32).
Accordingly, the invention includes a packaged pharmaceutical composition for
inhibiting amyloid deposition in a subject, comprising a container holding a
therapeutically
effective amount of a therapeutic formulation as described herein; and
instructions for using
the compound for inhibiting amyloid deposition in a subject. In certain
embodiments, the
disease related to such amyloid deposition is selected from the group
consisting of
Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis,
macular
degeneration, Down's syndrome, Mild Cognitive Impairment, type II diabetes,
and hereditary
cerebral hemorrhage.
The term "container" includes any receptacle for holding the therapeutic
formulation.
For example, in one embodiment, the container is the packaging that contains
the
formulation. In other embodiments, the container is not the packaging that
contains the
formulation, i.e., the container is a receptacle, such as a box or vial that
contains the packaged
formulation or unpackaged formulation and the instructions for use of the
formulation.
Moreover, packaging techniques are well known in the art. It should be
understood that the
instructions for use of the therapeutic formulation may be contained on the
packaging
containing the therapeutic formulation, and as such the instructions form an
increased
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functional relationship to the packaged product. However, it should be
understood that the
instructions can contain information pertaining to the compound's ability to
perform its
intended function, e.g., reduce or prevent gastrointestinal intolerance.
In another embodiment, the invention includes a packaged pharmaceutical
composition for treating amyloidosis in a subject, comprising a container
holding a
therapeutically effective amount of a therapeutic formulation as described
herein; and
instructions for using the compound for treating amyloidosis in a subject.
In yet another embodiment, the invention includes a packaged pharmaceutical
composition for treating a viral infection, comprising a container holding a
therapeutically
effective amount of a therapeutic formulation as described herein; and
instructions for using
the compound for treating the viral infection.
Another embodiment of the invention pertains to a packaged pharmaceutical
composition for treating a bacterial infection, comprising a container holding
a therapeutically
effective amount of a therapeutic formulation of the invention; and
instructions for using the
therapeutic compound for treating the bacterial infection.
Another embodiment of the invention pertains to a packaged pharmaceutical
composition for inhibiting the binding of a chemokine to a glycosaminoglycan,
comprising a
container holding a therapeutically effective amount of a therapeutic
formulation of the
invention; and instructions for using the therapeutic compound for inhibiting
the binding of a
chemokine to a glycosaminoglycan.
The therapeutic formulations of the invention may also include combinations of
two
or more therapeutic compounds. Accordingly, the invention relates to a
therapeutic
formulation for the treatment of Alzheimer's disease comprising 3-amino-1-
propanesulfonic
acid and a second drug that targets additional symptoms, e.g., secondary
symptoms of
Alzheimer's disease. In certain embodiments, the "second drug" may be a
cholinesterase
inhibitor, such as an acetyl-cholinesterase or butyryl-cholinesterase
inhibitor, e.g., tacrine,
donepezil, rivastigmine, or galantamine. In another embodiment, the second
drug may be an
NMDA receptor antagonist, such as memantine. In yet another embodiment, the
second drug
may be an antioxidant, vitamin E, estrogen, a nonsteroidal anti-inflammatory
agent (e.g.,
aspirin or naproxen), a cholesterol modifying agent such as statin, or ginkgo
biloba. The
methods for administering the active agent as discussed herein can - when used
in
conjunction with another therapeutic agent - be used as a first line therapy
or otherwise, e.g.,
as a second line therapy to other therapeutics, including known effective
treatment methods.
The therapeutic formulation of the invention may further include a
pharmaceutically
acceptable vehicle. As used herein "pharmaceutically acceptable vehicle"
includes any and
all coatings, antibacterial and antifungal agents, and absorption delaying
agents, and the like
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that are compatible with the activity of the compound, are physiologically
acceptable to the
subject, and that do not significantly affect the ability of the therapeutic
formulation to
perform its intended function or do not significantly affect the ability of
the therapeutic
formulation to reduce or prevent gastrointestinal intolerance. Supplementary
active
compounds can also be incorporated into the compositions as long as they do
not significantly
affect the ability of the therapeutic formulation to reduce or prevent nausea.
Active compounds are administered at a therapeutically effective dosage
sufficient to
inhibit amyloid deposition in a subject. A "therapeutically effective dosage"
preferably
inhibits amyloid deposition by at least about 20%, more preferably by at least
about 40%,
even more preferably by at least about 60%, and still more preferably by at
least about 80%
relative to untreated subjects. The ability of a compound to inhibit amyloid
deposition can be
evaluated in an animal model system that may be predictive of efficacy in
inhibiting amyloid
deposition in human diseases. Alternatively, the ability of a compound to
inhibit amyloid
deposition can be evaluated by examining the ability of the compound to
inhibit an
interaction between an arnyloidogenic protein and a basement membrane
constituent, e.g., as
described in U.S. Patent No. 5,164,295, which is hereby expressly incorporated
herein by
reference, or by the mass spectroscopy assay described in Example 5.
The term "subject" includes living organisms in which amyloidosis can occur,
or
which are susceptible to amyloid diseases, e.g., Alzheimer's disease, Down's
syndrome, Mild
Cognitive Impairment, CAA, dialysis-related (~i2M) amyloidosis, secondary (AA)
amyloidosis, primary (AL) amyloidosis, hereditary amyloidosis, diabetes, etc.
Examples of
subjects include humans, monkeys, cows, sheep, goats, dogs, and cats. The
language
"subject" includes animals (e.g., mammals, e.g., cats, dogs, horses, pigs,
cows, goats, sheep,
rodents, e.g., mice or rats, rabbits, squirrels, bears, primates (e.g.,
chimpanzees, monkeys,
gorillas, and humans)), as well as chickens, ducks, peking ducks, geese, and
transgenic
species thereof.
In certain embodiments of the invention, the subject is in need of treatment
by the
methods of the invention, and is selected for treatment based on this need. A
subject in need
of treatment is art-recognized, and includes subjects that have been
identified as having a
disease or disorder related to amyloids or amyloid-deposition or amyloidosis,
having a
symptom of such a disease or disorder, or at risk of such a disease or
disorder, and would be
expected, based on diagnosis, e.g., medical diagnosis, to benefit from
treatment (e.g., curing,
healing, preventing, alleviating, relieving, altering, remedying,
ameliorating, improving, or
affecting the disease or disorder, the symptom of the disease or disorder, or
the risk of the
disease or disorder).
Administration of the compositions of the present invention to a subject to be
treated
can be carried out using known procedures, at dosages and for periods of time
effective to
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inhibit amyloid deposition in the subject. An effective amount of the
therapeutic compound
necessary to achieve a therapeutic effect may vary according to factors such
as the amount of
amyloid already deposited at the clinical site in the subject, the age, sex,
and weight of the
subject, and the ability of the therapeutic compound to inhibit amyloid
deposition in the
subject. Dosage regimens can be adjusted to provide the optimum therapeutic
response. For
example, several divided doses may be administered daily or the dose may be
proportionally
reduced as indicated by the exigencies of the therapeutic situation. A non-
limiting example
of an effective dose range for a therapeutic compound of the invention (e. g.,
3-amino-
1-propanesulfonic acid) is between 1 and 500 mg/kg of body weighdper day. In
another non-
limiting example, the active agent of 3-amino-1-propanesulfonic acid or
pharmaceutically
acceptable salt thereof is provided in a formulation in an amount of about 200
mg or less,
preferably from about 50 to about 150 mg and particularly about 50, about 100
or about 150
mg. In a further aspect, the invention is directed to methods for daily or
twice daily
administering of such formulations to a patient in need thereof. One of
ordinary skill in the
art would be able to study the relevant factors and make the determination
regarding the
effective amount of the therapeutic compound without undue experimentation.
Actual dosage levels of the active ingredients in the pharmaceutical
compositions of
this invention may be varied so as to obtain an amount of the active
ingredient that is
effective to achieve the desired therapeutic response for a particular
patient, composition, and
mode of administration, without being toxic to the patient.
In particular, the selected dosage level will depend upon a variety of factors
including
the activity of the particular compound of the present invention employed, the
time of
administration, the rate of excretion of the particular compound being
employed, the duration
of the treatment, other drugs, compounds or materials used in combination with
the particular
compound employed, the age, sex, weight, condition, general health and prior
medical history
of the patient being treated, and like factors well known in the medical arts.
A medical doctor, e.g., physician or veterinarian, having ordinary skill in
the art can
readily determine and prescribe the effective amount of the pharmaceutical
composition
required. For example, the physician or veterinarian could start doses of the
compounds of
the invention employed in the pharmaceutical composition at levels lower than
that required
in order to achieve the desired therapeutic effect and gradually increase the
dosage until the
desired effect is achieved.
The regimen of administration can affect what constitutes an effective amount.
The
therapeutic formulations can be administered to the subject either prior to or
after the onset of
amyloidosis. Further, several divided dosages, as well as staggered dosages,
can be
administered daily or sequentially, or the dose can be continuously infused,
or can be a bolus
injection. Further, the dosages of the therapeutic formulations can be
proportionally
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increased or decreased as indicated by the exigencies of the therapeutic or
prophylactic
situation.
In particular embodiments, it is especially advantageous to formulate
compositions in
dosage unit form for ease of administration and uniformity of dosage. Dosage
unit form as
used herein refers to physically discrete units suited as unitary dosages for
the subjects to be
treated; each unit containing a predetermined quantity of therapeutic compound
calculated to
produce the desired therapeutic effect in association with the required
pharmaceutical vehicle.
The specification for the dosage unit forms of the invention are dictated by
and directly
dependent on (a) the unique characteristics of the therapeutic compound and
the particular
therapeutic effect to be achieved, and (b) the limitations inherent in the art
of
compounding/formulating such a therapeutic compound for the treatment of
amyloid
deposition in subjects.
A further aspect of the invention includes pharmaceutical compositions for
treating
amyloidosis; inhibiting amyloid deposition; or preventing or treating amyloid-
related disease,
e.g., A(3-related disease, e.g., Alzheimer's disease, cerebral amyloid
angiopathy, inclusion
body myositis, macular degeneration, Down's syndrome, Mild Cognitive
Impairment, and
hereditary cerebral hemorrhage. The therapeutic formulations described
hereinbefore, can be
incorporated into a pharmaceutical composition containing a pharmaceutically
acceptable
vehicle and an amount of a therapeutic compound formulated to significantly
reduce or
prevent gastrointestinal intolerance, in an amount sufficient to treat or
inhibit amyloidosis;
inhibit amyloid deposition; or prevent or treat amyloid-related disease.
In one embodiment, the pharmaceutical compositions of the invention include a
therapeutic compound having the formula 3-amino-1-propanesulfonate / X, where
X is an
ester or a counter cation, wherein the ester or counter canon includes alcohol
radicals or
positively charged atoms and moieties, respectively, that do not significantly
affect the ability
of the therapeutic formulation to reduce or prevent gastrointestinal
intolerance. In a preferred
embodiment, the cationic group is hydrogen, H'~, and the compound is 3-amino-
1-propanesulfonic acid. For example, the non-hygroscopic nature of the acid
form makes it
more stable and desirable as active pharmaceutical ingredient.
In yet another embodiment, the invention is a method of formulating a
gastrointestinal
intolerance enhanced pharmaceutical composition comprising: combining a pre-
selected
therapeutic compound with a pharmaceutically acceptable carrier, wherein the
therapeutic
compound is pre-selected for its ability to significantly reduce or prevent
gastrointestinal
intolerance, forming a gastrointestinal intolerance enhanced pharmaceutical
composition.
The language "gastrointestinal intolerance enhanced pharmaceutical
composition"
includes pharmaceutical compositions containing therapeutic compounds of the
invention that
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have been chosen by pre-selecting the compound based on its ability to
significantly reduce or
prevent gastrointestinal intolerance.
IV. Administration
Formulations of the present invention include those suitable for oral
administration.
The formulations may conveniently be presented in unit dosage form and may be
prepared by
any methods well known in the art of pharmacy. The amount of active ingredient
which can
be combined with a Garner material to produce a single dosage form will
generally be that
amount of the compound which produces a therapeutic effect. Generally, out of
one hundred
percent, this amount will range from about 1 percent to about ninety-nine
percent of active
ingredient, preferably from about 5 percent to about 70 percent, most
preferably from about
10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of
bringing
into association a compound of the present invention with the carrier and,
optionally, one or
more accessory ingredients. In general, the formulations are prepared by
uniformly and
intimately bringing into association a compound of the present invention with
liquid carriers,
or finely divided solid carriers, or both, and then, if necessary, shaping the
product.
Formulations of the invention suitable for oral administration may be in the
form of
capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually
sucrose and acacia or
tragacanth), powders, granules, pellets, e.g., coated (e.g., enteric coated)
or uncoated, or as a
solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-
water or water-
in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an
inert base, such as
gelatin and glycerin, or sucrose and acacia) or as mouth washes and the like,
each containing
a predetermined amount of a compound of the present invention as an active
ingredient. A
compound of the present invention may also be administered as a bolus,
electuary or paste.
In solid dosage forms of the invention for oral administration (capsules,
tablets, pills,
dragees, powders, granules, pellets, and the like), the active ingredient is
mixed with one or
more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium
phosphate, or
any of the following: fillers or extenders, such as starches, lactose,
sucrose, glucose, mannitol,
or silicic acid; binders, such as, for example, carboxymethylcellulose,
alginates, gelatin,
polyvinyl pyrrolidone, sucrose or acacia; humectants, such as glycerol;
disintegrating agents,
such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid,
certain silicates,
and sodium carbonate; solution retarding agents, such as paraffin; absorption
accelerators,
such as quaternary ammonium compounds; wetting agents, such as, for example,
cetyl
alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite
clay; lubricants,
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such as talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl
sulfate, and mixtures thereof; and coloring agents. In the case of capsules,
tablets and pills,
the pharmaceutical compositions may also comprise buffering agents. Solid
compositions of
a similar type may also be employed as fillers in soft and hard-filled gelatin
capsules using
such excipients as lactose or milk sugars, as well as high molecular weight
polyethylene
glycols and the like. The therapeutic compounds of the invention are effective
when
administered orally. Accordingly, a preferred route of administration is oral
administration.
The therapeutically active compound may be coated in a material to protect the
compound
from the action of acids and other natural conditions which may inactivate the
compound.
The compounds of the invention can be formulated to ensure proper distribution
in vivo. For
example, the blood-brain barner (BBB) excludes many highly hydrophilic
compounds; and to
ensure that the therapeutic compounds of the invention cross the BBB, they can
be
formulated, for example, in liposomes. For methods of manufacturing liposomes,
see, e.g.,
U.S. 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or
more
moieties which are selectively transported into specific cells or organs
("targeting moieties"),
thus providing targeted drug delivery (see, e.g., V. V. Ranade (1989) J. Clin.
Pharmacol.
29:685). Exemplary targeting moieties include folate or biotin (see, e.g.,
U.S. 5,416,016 to
Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun.
153:1038); antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357:140; M.
Owais et al.
(1995) Antimicrob. Agents Chemother. 39:180); surfactant protein A receptor
(Briscoe et al.
(1995) Am. J. Physiol. 1233:134); gp120 (Schreier et al. (1994) J. Biol. Chem.
269:9090);
see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett. 346:123; J. J.
Killion; I. J. Fidler
(1994) Immunomethods 4:273.
To administer the therapeutic compound it may be necessary to coat the
compound
with, or co-administer the compound with, a material to prevent its
inactivation. For example,
the therapeutic compound may be administered to a subject in an appropriate
carrier, for
example, liposomes, or a diluent. Liposomes include water-in-oil-in-water CGF
emulsions as
well as conventional liposomes (Strejan, et al., J Neuroimmunol. 7, 27
(1984)).
The therapeutic compound can be orally administered, for example, with an
inert
diluent or an assimilable edible earner. The therapeutic compound and other
ingredients may
also be enclosed in a hard or soft shell gelatin capsule, compressed into
tablets, or
incorporated directly into the subject's diet. For example, therapeutic
formulations, such as
enteric coated pellets, could be compacted into tablets or encapsulated into
hard gelatin
capsule. In particular embodiments of the invention, the pellets useful in the
present
invention may be, for example, 0.05 mm - 3 mm, e.g., about 0.8-1.8 mm.
Moreover, in
certain embodiments these pellets can be formulated to (a) provide for instant
or rapid drug
release (i.e., have no coating on them); (b) be coated, e.g., to provide for
sustained drug
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release over time; or (c) be coated with an enteric coating for better
gastrointestinal
tolerability.
The pharmaceutical formulations according to the invention can be provided in
any
dosage unit (e.g., tablets, capsules, caplets, transdennal patch, etc.); or in
two or more of the
same or different such units; and/or as individual components of a given
dosage unit (e.g.,
layers, beads, compartments, matrices, coatings, shapes, etc.) which cooperate
on
administration to achieve the release and/or concentration profile properties
desired for any of
the embodiments of this invention. Thus, included are single dosage units,
such as multi-
layer, multi-bead, multi-matrix, multi-compartment forms which achieve, in
general, a
controlled (e.g., pulsed, sustained, extended, delayed, slow, first order,
second order, etc.)
release over an entire day, or achieve preferred profiles in accordance with
the invention; and
multiple dosage units (to be simultaneously or sequentially administered),
typically associated
together, e.g., in the form of a kit containing the multiple units, identified
in a manner which
indicates the time of day or relative time order in which the units are to be
administered. One
of many such kits is a conventional blister pack (or other pouch or container
system)
containing the multiple units and instructions or notices or indicia regarding
the timing and
order of administration. Other manners of identifying the time of day and/or
order of
administration can include unit shape, color, size, etc and combinations
thereof.
Formulations for achieving the foregoing dosing regimens are conventional.
These
can use immediate, controlled, sustained, extended, delayed, pulsatile,
osmotic etc.
technologies, alone or in combination to achieve the desired regimens.
Examples of potential
formulations and preparations are contained, for example, in the Handbook of
Pharmaceutical
Excipents, American Pharmaceutical Association 4a' edition, 2003 (Rowe,
Sheskey and
Weller); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and
Schwarts,
editors) current edition, published by Marcel Dekker, Inc., as well as
Remington's
Pharmaceutical Sciences (A. Gennaro, editor, 20th edition, 2000). Where pulses
in an
extended release capsule or tablet are to be employed, the methods and
formulations
described in USP 5,837,284 can be used, for example, including conventional
pulsing
techniques, such as enteric or other coatings, osmotic systems, and many
others. Where
smoother release profiles are to be achieved, conventional sustained or
controlled release
methods can be used; see, e.g., in R.K. Chang and J.R. Robinson, chapter 4:
"Sustained Drug
Release from Tablets and Particles Through Coating," in Pharmaceutical Dosage
Forms:
Tablets, volume 3, edited by H.A. Lieberman, L. Lachman, and J.B. Schwartz,
Marcel
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Dekker, Inc., 1991; R.J. Campbell and G.L. Sackett, chapter 3: "Film coating,"
in
Pharmaceutical Unit O .Lerations: Coatine, edited by K.E. Avis, A.J. Shukla,
and R.K. Chang,
Interpharm Press, Inc., 1999. All of these disclosures are entirely
incorporated by reference
herein.
For example, the active agents can be provided in the form of beads, e.g.,
having a
core which is optionally coated with a coating which allows the release of the
agent
immediately or over time, such as a pharmaceutically acceptable water-
insoluble or water
soluble film former alone or with a dissolution regulating agent etc.. See,
e.g., USP
4,728,512. A biphasic or multiphasic release profile can be achieved by
combining the
immediate-release beads with delayed, sustained or other controlled release
beads or by
providing various extended release beads with differing release profiles.
Beads can be prepared by coating conventional drug-containing cores with a
water-
insoluble polymer, or a combination of water-insoluble polymers, or a
combination of water-
insoluble and water-soluble polymers. This may be a combination of layers, or
a combination
of polymers in a single coating. The resultant beads (or tiny tablets) can
then be placed in a
capsule. Other than beads in a capsule shell, tablets in a capsule shell
(e.g., one or more
immediate-release tablet and one or more delayed, sustained release tablet in
a capsule shell)
also can be used to attain the desired release profile.
Various polymeric materials can be used to achieve the desired type of pattern
of
release, e.g., immediate, sustained, delayed etc. release. For example, a
multiple dosage form
(e.g., as discussed below) can deliver rapid and complete dosages of active
agent to a
recipient multiple times over a period of hours with a single oral
administration, if it is
desired to combine dosages in a single unit; additionally, doses with
sustained or delayed
release function can be combined with each other or with doses having
immediate release
functionality.
Examples of possible bead constructions are plentiful and include the
following:
Sugar core bead, coated with active agent and then coated with polymer and/or
with mix of active agent and polymer or any different order of such layers on
the
core, within each case, selected active agent concentrations of components in
the
layers.
Bead containing active agent core, coated with polymer, and/or with mix of
active agent and polymer or any different order of such layers on the core,
within
each case, selected active agent concentrations of components in the layer.
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Tablet or capsule containing multiple types of beads as described above having
differing timing of release or different rates of release of active agent.
Matrix beads can also be used, i.e., not having any layers to achieve
sustained or
delayed release. The components used in such matrices are chosen from
conventional
sustained release or delayed release polymers.
Details of using the foregoing constructs and others to achieve a desired
release
profile as discussed above are fully conventional and can be determined by
those of skill in
the art with at most a few routine parametric experiments, and conventional
adjustments, e.g.,
involving identities of polymers and mixtures thereof, relative amounts of
components,
coating thicknesses, bead diameters, number of layers and compositions
thereof, etc. Thus,
for example, for a given construct, in vitro dissolution profiles as described
herein can be
determined. Fully conventional formulation and dissolution profile adjustments
can be made
routinely. Formulations having the desired in vitro release profiles produce
the desired
plasma concentration levels. These plasma profiles will be correlated with the
release
profiles in view of the usual factors, e.g., in vivo dissolution and
absorption properties, active
agent half-lives, etc., which correlation is well understood in the art.
Suitable materials which can be used to achieve formulations having such
release
profiles are well known and include but are not limited to polyvinyl acetate,
cellulose acetate,
cellulose acetate lattices, cellulose acetate butyrate, cellulose acetate
propionate, ethyl
cellulose, fatty acids and their esters, alkyl alcohols, waxes, zein
(prolamine from corn), and
aqueous polymeric dispersions such as the commercially available Eudragit~,
Aquacoat~,
Surelease~, Kollicoat~, etc., products.
The agent-containing particles may also be incorporated into a tablet, in
particular by
incorporation into a tablet matrix, which rapidly disperses the particles
after ingestion. In
order to incorporate these particles into such a tablet, a filler/binder must
be added to a tablet
that can accept the particles, but will not allow their destruction during the
tableting process.
Materials that are suitable for this purpose include, but are not limited to,
microcrystalline
cellulose (e.g., AVICEL~), soy polysaccharide (e.g., EMCOSOYC~), pre-
gelatinized starches
(e.g., STARCH~ 1500, NATIONAL~ 1551), and polyethylene glycols (e.g.,
CARBOWAX~). The materials are typically present in the range of 5-75% (w/w),
with a
preferred range generally of 25-50% (w/w).
In addition, disintegrants can optionally be added in order to disperse the
beads once
the tablet is ingested. Suitable disintegrants include, but are not limited
to: cross-linked
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sodium carboxymethyl cellulose (e.g., AC-DI-SOLC~1), sodium starch glycolate
(e.g.,
EXPLOTAB~, PRTMOJEL~), and cross-linked polyvinylpolypyrrolidone (e.g.,
Plasone-XL).
These materials are typically present in the rate of 3-15% (w/w), with a
preferred range
generally of 5-10% (w/w).
Lubricants can also optionally be added to assure proper tableting, and these
can
include, but are not limited to: magnesium stearate, calcium stearate, stearic
acid,
polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable
oil. These
lubricants are typically present in amounts from 0.1-10% (w/w), with a
preferred range
generally of 0.3-3.0% (w/w).
Where immediate release is not desired, for example, various enteric
materials, e.g.,
cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate,
polyvinyl acetate
phthalate, and the EUDRAGITC~ and ACRYLEZE~ acrylic polymers, can be used as
gastroresistant, enterosoluble coatings for drug release in the intestine when
desired. The
enteric materials, which are soluble at higher pH values, are frequently used
for colon-specific
delivery systems and are entirely conventionally employable in the systems of
this invention.
The enteric polymers used in this invention can also be modified
conventionally by mixing
with other known coating products that are not pH sensitive. Examples of such
coating
products include the neutral methacrylic acid esters with a small portion of
trimethylammonioethyl methacrylate chloride, which are commercially available,
e.g.,
EUDRAGIT~ RS and EUDRAGIT~ RL; neutral ester dispersions without any
functional
groups, e.g., EUDRAGTTC~? NE30D and EUDRAGIT~ NE30; and other pH independent
coating products.
A conventional protective coating layer may also be applied immediately
outside the
core, either a drug-containing matrix core or a drug-layered core, by
conventional coating
techniques such as pan coating or fluid bed coating using solutions of
polymers in water or
suitable organic solvents or by using aqueous polymer dispersions. Suitable
materials for the
protective layer include cellulose derivatives such as hydroxyethyl cellulose,
hydroxypropyl
cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone,
polyvinylpyrrolidone/vinyl
acetate copolymer, ethyl cellulose aqueous dispersions, polyvinyl acetate
(e.g.,
AQUACOAT~, SURELEASE~), EUDRAG1T~'s, OPADRY~ and the like. Typical
coating levels are from 1 to 6%, in.general, preferably 2-4% (w/w).
An overcoating layer can further optionally be applied to the compositions of
the
present invention. OPADRY~, OPADRY II~ (Colorcon) and corresponding color and
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colorless grades from Colorcon can be used to protect the pellets from being
tacky and
provide colors to the product. Typical levels of protective or color coating
are from 1 to 6%,
in general preferably 2-3% (w/w). Many ingredients can be incorporated into
the overcoating
formula, for example to provide a quicker (immediate) release, such as
plasticizers:
acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate,
dibutylsebacate, triacetin,
polyethylene glycols, propylene glycol and the others; lubricants: talc,
colloidal silica dioxide,
magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate,
and the like.
Optional modifying components of a protective layer which can be used over the
enteric or other coatings include a water penetration barrier layer (semi-
permeable polymer)
which can be successively coated after the enteric or other coating to reduce
the water
penetration rate through the enteric coating layer and thus increase the lag
time of the drug
release. Sustained-release coatings commonly known to one skilled in the art
can be used for
this purpose by conventional coating techniques such as pan coating or fluid
bed coating
using solutions of polymers in water or suitable organic solvents or by using
aqueous polymer
dispersions. For example, the following materials can be used, but not limited
to: cellulose
acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl
cellulose, fatty acids and
their esters, waxes, zero, and aqueous polymer dispersions such as
EUDRAGIT~'s, e.g., RS,
RL 30D, NE 30D, AQUACOAT~, SURELEASE~, cellulose acetate latex, etc.
Combinations of the above polymers and hydrophilic polymers such as
hydroxyethyl
cellulose, hydroxypropyl cellulose (KLUCEL~, Hercules Corp.), hydroxypropyl
methylcellulose (METHOCEL~, Dow Chemical Corp.), and polyvinylpyrrolidone can
also
be used.
For oral therapeutic administration, the therapeutic compound may be
incorporated
with excipients and used in the form of ingestible tablets, buccal tablets,
troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. The percentage of the
therapeutic
compound in the compositions and preparations may, of course, be varied. The
amount of the
therapeutic compound in such therapeutically useful compositions is such that
a suitable
dosage will be obtained.
The term "pharmaceutically acceptable carrier" includes a pharmaceutically
acceptable material, composition or vehicle, such as a liquid or solid filler,
diluent, excipient,
solvent or encapsulating material, involved in carrying or transporting a
compounds) of the
present invention within or to the subject such that it can perform its
intended function.
Typically, such compounds are carried or transported from one organ, or
portion of the body,
to another organ, or portion of the body. Each carrier must be "acceptable" in
the sense of
being compatible with the other ingredients of the formulation, not injurious
to the patient,
and in the sense that it does not affect the ability of the therapeutic
formulation to reduce or
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prevent gastrointestinal intolerance. Some examples of materials which can
serve as
pharmaceutically acceptable carriers include: sugars, such as lactose, glucose
and sucrose;
starches, such as corn starch and potato starch; cellulose, and its
derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt;
S gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils,
such as peanut oil,
cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as
propylene glycol; polyols, such as glycerin, sorbitol, mannitol and
polyethylene glycol; esters,
such as ethyl oleate and ethyl laurate; agar; buffering agents, such as
magnesium hydroxide
and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution;
ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible
substances
employed in pharmaceutical formulations known in the art.
The term "vehicle" is intended to encompass any substance which is
pharmaceutically
or pharmacologically acceptable.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents, coating
agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can also be
present in the
compositions.
Examples of pharmaceutically acceptable antioxidants include: water soluble
antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate,
sodium
metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as
ascorbyl palmitate,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT~, lecithin,
propyl gallate,
alpha-tocopherol, and the like; and metal chelating agents, such as citric
acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric
acid, and the like.
A tablet may be made by compression or molding, optionally with one or more
accessory ingredients. Compressed tablets may be prepared using binder (for
example, gelatin
or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,
disintegrant (for
example, sodium starch glycolate or cross-linked sodium carboxymethyl
cellulose), surface-
active or dispersing agent. Molded tablets may be made by molding in a
suitable machine a
mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions
of the
present invention, such as dragees, capsules, pills, pellets, and granules,
may optionally be
scored or prepared with coatings and shells, such as enteric coatings and
other coatings well
known in the pharmaceutical-formulating art. They may also be formulated so as
to provide
slow or controlled release of the active ingredient therein using, for
example,
hydroxypropylmethyl cellulose in varying proportions to provide the desired
release profile,
other polymer matrices, liposomes or microspheres. They may be sterilized by,
for example,
filtration through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form
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of sterile solid compositions which can be dissolved in sterile water, or some
other sterile
injectable medium immediately before use. These compositions may also
optionally contain
opacifying agents, and/or may contain agents that release the active
ingredients) only, or
preferentially, in a certain portion of the gastrointestinal tract,
optionally, in a delayed
manner. Examples of embedding compositions which can be used include polymeric
substances and waxes. The active ingredient can also be in micro-encapsulated
form, if
appropriate, with one or more of the above-described excipients.
Powders can contain, in addition to a compound of this invention, excipients
such as
lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and
polyamide powder, or
mixtures of these substances.
Liquid dosage forms for oral administration of the compounds of the invention
include pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions,
syrups and elixirs. In addition to the active ingredient, the liquid dosage
forms may contain
inert diluents commonly used in the art, such as, for example, water or other
solvents,
solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate,
ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol,
tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of
sorbitan, and mixtures
thereof. Besides inert diluents, the oral compositions can also include
adjuvants such as
wetting agents, emulsifying and suspending agents, sweetening, flavoring,
coloring,
perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending
agents as,
for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, and
mixtures thereof.
These compositions may also contain adjuvants such as preservatives, wetting
agents,
emulsifying agents and dispersing agents. Prevention of the action of
microorganisms may be
ensured by the inclusion of various antibacterial and antifungal agents, for
example, paraben,
chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to
include isotonic
agents, such as sugars, sodium chloride, and the like into the compositions.
In addition,
prolonged absorption of the injectable pharmaceutical form may be brought
about by the
inclusion of agents that delay absorption such as aluminum monostearate and
gelatin.
The compositions of this invention can also be administered topically to a
subject,
e.g., by the direct laying on or spreading of the composition on the epidermal
or epithelial
tissue of the subject, or transdermally via a "patch". Such compositions
include, for example,
lotions, creams, solutions, gels and solids. These topical compositions
preferably comprise
an effective amount, usually at least about 0.1 %, and preferably from about 1
% to about 5 %,
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of a compound of the invention. Suitable carriers for topical administration
preferably remain
in place on the skin as a continuous film, and resist being removed by
perspiration or
immersion in water. Generally, the Garner is organic in nature and capable of
having the
therapeutic compound dispersed or dissolved therein. The carrier may include
pharmaceutically acceptable emolients, emulsifiers, thickening agents,
solvents and the like.
In one embodiment, the pharmaceutical formulation comprises greater than about
0.1%" e.g., greater than about 1%, e.g., greater than about 2%, e.g., greater
than about 3%,
e.g., greater than about 4%, e.g., greater than about 5%, e.g., greater than
about 10%, e.g.,
greater than about 20%, e.g., greater than about 30%, e.g., greater than about
40%, e.g.,
greater than about 50%, e.g., greater than about 60%, e.g., greater than about
70%, e.g.,
greater than about 80%, e.g., greater than about 90%, e.g., greater than about
95%, e.g.,
greater than about 99%, of a therapeutic compound, e.g., an alkylsulfonic
acid, e.g., a
3-amino-1-propanesulfonic acid compound, by weight of the formulation. In a
specific
embodiment, the pharmaceutical formulation comprises about 12.6% ~ 0.5% of the
therapeutic compound by weight of the formulation. In another specific
embodiment, the
pharmaceutical formulation comprises about 95.2% ~ 0.5% of the therapeutic
compound by
weight of the formulation. The remainder of the pharmaceutical formulation may
be
comprised of additional agents as described herein.
In another embodiment, the pharmaceutical formulation comprises greater than
about
1%, e.g., greater than about 2%, e.g., greater than about 3%, e.g., greater
than about 4%,
e.g., greater than about 5%, e.g., greater than about 6%, e.g., greater than
about 7%, e.g.,
greater than about 8%, e.g., greater than about 9%, e.g., greater than about
10%, e.g., greater
than about 20%, e.g., greater than about 30%, e.g., greater than about 40%,
e.g., greater than
about 50%, e.g., greater than about 60%, e.g., greater than about 70%, e.g.,
greater than about
80%, e.g., greater than about 90%, e.g., greater than about 95%, e.g., greater
than about 99%,
of an additional agent, e.g., an agent that modifies the release of the
therapeutic compound or
an enteric coating, by weight of the formulation. It should be understood that
these
percentages are ranges that apply to the one or more additional agents of the
formulation,
independently or in combination. In certain embodiments the additional agent
may be used in
the therapeutic formulation to impart favorable properties, e.g., to reduce or
prevent
gastrointestinal intolerance independently or in conjunction with other
methods of reducing or
preventing intolerance. Exemplary additional agents are described herein. For
example, to
protect against any possible gastrointestinal intolerance that could result
from the therapeutic
formulation, the tablets may be enteric-coated or a modified-release agent may
be added to
control any rapid release of the therapeutic compound in the stomach or
intestine. In a
specific embodiment, the pharmaceutical formulation comprises about 9.3 % ~
0.5% of the
additional agent by weight of the formulation. In another specific embodiment,
the
pharmaceutical formulation comprises about 8.8 % ~ 0.5% of the additional
agent by weight
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of the formulation. In another specific embodiment, the pharmaceutical
formulation
comprises about 5.6 % ~ 0.5% of the additional agent by weight of the
formulation.
In specific embodiments of the invention, the therapeutic compound is
administered
with an agent selected from the group consisting of an agent that modifies the
release of the
therapeutic compound, e.g., hydroxypropylmethylcellulose (HPMC), a
glidanddiluent, e.g.,
silicated mycrocrystalline, a filler, e.g., dibasic calcium phosphate, a
binder/desintegrant, e.g.,
Starch~ 1500, a lubricant, e.g., stearic acid powder or magnesium stearate, a
subcoat, e.g.,
Opadry~ II White, a topcoat, e.g., Opadry~ II White or Opadry~ Clear, an
enteric coat, e.g.,
Acryleze~, and any combination thereof. The following materials are available
from
Colorcon (West Point, PA): Starch~ 1500, Opadry~ II White, Opadry~ Clear,
Acryleze~.
Several embodiments of the invention are discussed below in the Examples
section.
Eauivalents
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation and the content of the instant specification, numerous
equivalents to
the specific procedures, embodiments, claims, and examples described herein.
Such
equivalents are considered to be within the scope of this invention and
covered by the claims
appended hereto.
It is to be understood that wherever values and ranges are provided herein,
e.g., in
ages of subject populations, dosages, and blood levels, all values and ranges
encompassed by
these values and ranges, are meant to be encompassed within the scope of the
present
invention. Moreover, all values that fall within these ranges, as well as the
upper or lower
limits of a range of values are also contemplated by the present application.
Brief Description of the Drawings
Figure 1 Change from Baseline CSF A(342 versus 3-APS doses
Figure 2 Effect of 3-APS on CSF A(34~,ao Ratio in Mild-to-Moderate AD Patients
-
Placebo vs. 150 mg BID
Figure 3 Effect of 3-APS on CSF AJ34vao Ratio in Mild-to-Moderate AD Patients
0 and
SOmg 3-APS
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Figure 4 Effect of 3-APS on CSF A~3ayao Ratio in Mild-to-Moderate AD Patients
100
and 150mg 3-APS
Incoruoration by Reference
The contents of all references, issued patents, and published patent
applications cited
throughout this application are hereby incorporated by reference. It should be
understood that
the use of any of the compounds described herein or in the applications
identified in "The
Related Applications" Section are within the scope of the present invention
and are intended
to be encompassed by the present invention and are expressly incorporated
herein at least for
these purposes, and are furthermore expressly incorporated for all other
purposes
Examples
The invention is further illustrated by the following examples which should
not be
construed as further limiting the subject invention.
Example 1- Gelatin Capsules for Oral Administration
The unit formula of 100 and 400 mg white gelatin capsules is presented in
Table 2.
Table 2: Unit Formula for 100 and 400 mg Gelatin Capsules
Ingredient Grade Function Capsules
(mg/capsule)
100 mg 400 mg
3-amino-1-propanesulfonicMS* Active Ingredient100 mg 400 mg
acid, sodium salt
Calcium carbonate NF Filler 4.45 17.8
Magnesium stearateNF I Lubricant 0.55 2.2
I
*MS: Manufacturer's Standard, NF: National Formulary; USP: United States
Pharmacopoeia.
Results from certain studies have shown that the administration of 3-amino-
1-propanesulfonic acid sodium salt in solid dosage form (capsules) was
associated with
gastrointestinal symptoms (i.e. nausea and vomiting). Further investigations
revealed that the
gastrointestinal symptoms were produced, at least in part, by a local
irritation due to the high
pH generated during the dissolution of amino-1-propanesulfonic acid sodium
salt into the
stomach. Additional experiments in dogs (in solid dosage form) have shown that
the free
acid was better tolerated than the sodium salt form. Furthermore, the non-
hygroscopic nature
of the acid form makes it desirable as active pharmaceutical ingredient. To
further protect
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against any possible gastrointestinal intolerance that could result from the
acid form, the
tablets were enteric-coated and a modified-release agent was added to control
any rapid
release of the drug in the stomach and the intestine, respectively.
Example 2 - Enteric-Coated Tablets
The 100 and 400 mg white enteric-coated tablets were prepared according to a
formulation in which the drug substance produced by a process utilizing ion-
exchange to
remove sodium was densified by granulation with water because of its low
density and
fluffiness. The unit formula of the 100 and 400 mg Enteric-Coated tablets is
presented in
Table 3.
Table 3: Unit Formula of 100 and 400 Enteric-Coated Tablets
Ingredient GradeFunction
Enteric-Coated
Tablet
(mg/tablet)
100 mg 400
mg
Core:
3-amino-1-propanesulfonic MS* Active Ingredient100.00 400.00
acid
Silicated mycrocrystallineNF Glidant/Diluent350.00 70.00
cellulose
Dibasic calcium phosphate USP Filler 158.40 112.00
HydroxypropylmethylcelluloseUSP Drug Release 70.00 70.00
(HPMC) Modifier
Starch~ 1500 NF Binder/Desintegrant11.10 37.50
Stearic acid powder NF Lubricant 7.00 7.00
Magnesium stearate NF Lubricant 1.80 0.018
Coating:
Opadry~ II White MS* Subcoat 14.00 14.00
Acryleze~ MS* Enteric Coat 42.00 42.00
Total Weight: - ~ . - 756.00 756.00
-~
*MS: Manufacturer's Standard, NF: National Formulary; USP: United States
Pharmacopoeia.
In vitro (dissolution rate) and PK data from 100 mg enteric-coated tablets
indicated
that these tablets would result in acceptable PK and good tolerability.
Example 3 - Modified-Release Coated Tablets
Clinical studies indicated that the role of the enteric-coating and drug
release modifier
would be significant in the pharmacokinetic (PK) profile of the drug product
as well as its
tolerability. Accordingly, in order to give particular pharmaceutical
performance in terms of
PK, tolerability and product stability, drug release modifier was formulated
into the tablet.
To improve physical stability of the product in terms of film coating
acceptability and
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moisture protection capability, under accelerated conditions, the enteric-
coating system was
modified by the increase in the amount of enteric-coating and the addition of
a topcoat.
A 50 mg strength modified-release coated tablet consisting of bulk substance
(3-amino-1-propanesulfonic acid) and inactive ingredients (silicated
mycrocrystalline
cellulose, dibasic calcium phosphate, hydroxypropylmethylcellulose, starch,
stearic acid,
magnesium stearate, as well as Opadry~ II white (subcoat and topcoat) and
Acryleze~) was
prepared. The unit formula of the SO mg modified-release coated tablet is
provided in Table
4.
Table 4: Unit Formula of 50 me Modified-Release Coated Tablets
quantity Gluantity
Ingredient GradeFunction per per
tablet batch
(mg) (kg)
Core:
3-amino-1-propanesulfonicMS* Active Ingredient50.00 0.500
acid
Silicated mycrocrystallineNF Glidant/Diluent174.73 1.746
cellulose
Dibasic calcium phosphateUSP Filler 79.42 0.794
HydroxypropylmethylcelluloseUSP Drug Release 35.00 0.350
(HPMC) Modifier
Starch~ 1500 NF Binder/Desintegrant5.55 0.056
Stearic acid powder NF Lubricant 3.50 0.036
Magnesium stearate NF Lubricant 1.80 0.018
Weight: 350.00 3.500
Coating:
Opadry~ II White MS* Subcoat 7.00 0.072
Acryleze~ MS* Enteric Coat 35.00 0.360
Opadry~ Clear MS* Topcoat 3.50 0.036
Total Weight: 395.50 3.974
*MS: Manufacturer's Standard, NF: National Formulary; USP: United States
Pharmacopoeia.
Example 4 - Modified-Release Coated Tablets
A slight modification to the coating in the formulation of Example 3 was made:
the
Opadry~ Clear used as the topcoat in Example 3 was replaced by Opadry~ II
White, which is
also used for the subcoat. Like Opadry~ Clear, Opadry~ II White is an HPMC-
based
preparation which functions in a sealing capacity and therefore equally
functions to enhance
the moisture protection capability of the enteric coat (Acryleze~). The
coating system
change of the topcoat was a process change that may be convenient for the
scale-up of the
product formulation size, i.e., to facilitate the transition from applying one
coat to the other
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during the coating process by preventing clogging of spray guns during the
transition from the
enteric coating step to the topcoat application step during the coating
process.
The unit formula for the 50 mg modified-release coated tablets are represented
in
Table 5.
Table 5: Unit Formula of 50 mg Modified-Release Coated Tablets
Ingredient Grade Function Quantity Gluantity
per tabletper
(mg) batch
(kg)
Core:
3-amino-1-propanesulfonicMS* Active ingredient50.00 0.500
acid
Silicated mycrocrystallineNF Glidant/Diluent174.73 1.746
cellulose
Dibasic calcium phosphateUSP Filler 79.42 0.794
HydroxypropylmethylcelluloseUSP Drug Release35.00 0.350
(HPMC) Modifier
Starch~ 1500 NF Binder/Desintegra5.55 0.056
nt
Stearic acid powder NF Lubricant 3.50 0.036
Magnesium stearate NF Lubricant 1.80 0.018
Weight: 350.00 3.500
Coating: -
Opadry~ II White MS* Subcoat 7.00 0.072
Acryleze~ MS* Enteric Coat35.00 0.360
Opadry~ II White MS* Topcoat 3.50 0.036
_
Total Weight: ~ 395.50 3.974
~
*MS: Manufacturer's Standard, NF: National Formulary; USP: United States
Pharmacopoeia.
The dissolution profile, carried out according to the USP method (USP 25,
Method B,
p. 2017), indicates that the dissolution rate for both of the 50 mg modified
release coated
tablets (Examples 3 and 4) is comparable.
In addition, in order to improve the stability of appearance i.e., whiteness,
the
following modified release coated tablet formulation was prepared, i.e., with
increased
Opadry~ II White:
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Table 6: Unit Formula of 50 m~ Modified-Release Coated Tablets
Ingredient Grade Function QuantityQuantity
per tabletper
(mg) batch
(kg)
Core:
3-amino-1-propanesulfonicMS* Active ingredient50.00 0.500
acid
Silicated mycrocrystallineNF Glidant/Diluent174.73 1.746
cellulose
Dibasic calcium phosphateUSP Filler 79.42 0.794
HydroxypropylmethylcelluloseUSP Drug Release 35.00 0.350
(HPMC) Modifier
Starch~ 1500 NF Binder/Desintegrant5.55 0.056
Stearic acid powder NF Lubricant 3.50 0.036
Magnesium stearate NF Lubricant 1.80 0.018
Weight: 350.00 3.500
Coating: -
Opadry~ II White MS* Subcoat 7.00 0.072
Acryleze~ MS* Enteric Coat 35.00 0.360
Opadry~ II White MS* Topcoat 7.00 0.072
Total Weight: 399.00 4.004
*MS: Manufacturer's Standard, NF: National Formulary; USP: United States
Pharmacopoeia.
Example 5 - Mass Spectrosco~y Assax
The binding of a compound to amyloid fibrils may be measured using a mass
spectroscopy ("MS") assay as described herein below.
Samples are prepared as aqueous solutions containing 20% ethanol, 200 ~,M of a
test
compound and 20 1tM of solubilized A~i40. The pH value of each sample is
adjusted to 7.4
(~0.2) by addition of 0.1 % aqueous sodium hydroxide. The solutions are then
analyzed by
electrospray ionization mass spectroscopy using a Waters ZQ 4000 mass
spectrometer.
Samples are introduced by direct infusion at a flow-rate of 25 N,L/min within
2 hours after
sample preparation. The source temperature is kept at 70 °C and the
cone voltage is 20 V for
all the analysis. Data is processed using Masslynx 3.5 software.
The resulting MS assay data provides insight into the ability of compounds to
bind to
A(3.
Example 6 - Modified-Release Coated Tablets-Selected Dose Strengths
Two additional dose strengths were prepared for the modified release coated
tablet
formulation of Example 4 (Table 6), i.e., 100 mg and 150 mg tablets. The
larger dose
strengths of the modified release coated tablets were selected and were
particularly useful for
the administration of therapeutically effective doses larger than 50 mg. In a
specific
embodiment, subjects that require a larger dose would require a smaller number
of pills to
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attain a prescribed dose, which would in turn lead to improved patient
compliance.
Accordingly, in certain embodiments of the invention, the dose is selected to
enhance patient
compliance.
For that reason, the 100 mg and 150 mg strength modified-release coated
tablets
consisting of bulk substance (3-amino-1-propanesulfonic acid) and inactive
ingredients
(silicated mycrocrystalline cellulose, dibasic calcium phosphate,
hydroxypropylmethylcellulose, starch, stearic acid, magnesium stearate, as
well as Opadry~
II white (subcoat and topcoat) and Acryleze~) were prepared. The unit formula
of the 100
mg modified-release coated tablet is provided in Table 7.
Table 7: Unit Formula of 10() mg Modified-Release Coated Tablets
Ingredient Grade Function QuantityProportion
per tablet
(mg)
Core:
3-amino-1-propanesulfonicMS* Active ingredient100.00 28.6
acid
Silicated mycrocrystallineNF Glidant/Diluent140.35 40.1
cellulose
Dibasic calcium phosphateUSP Filler 63.80 18.2
HydroxypropylmethylcelluloseUSP Drug Release
(HPMC) Modifier 35.00 10.0
Starch~ 1500 NF Binder/Desintegrant5.55 1.6
Stearic acid powder NF Lubricant 3.50 1.0
Magnesium stearate NF Lubricant 1.80 0.5
Weight: 350.00 100.0
Coating**: -
Opadry~ II White MS* Subcoat 7.00 2.0
Acryleze~ MS* Enteric Coat 35.00 10.0
Opadry~ II White MS* Topcoat 7.00 2.0
Total Weight: 399.00 114.0
*MS: Manufacturer's Standard, NF: National Formulary; USP: United States
Pharmacopoeia.
** Several processing steps involved the evaporation of purified water
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The unit formula of the 150 mg modified-release coated tablet is provided in
Table 8.
Table 8: Unit Formula of 150 mg Modified-Release Coated Tablets
Ingredient Grade Function QuantityProportion
per tablet
(mg)
Core:
3-amino-1-propanesulfonicMS* Active ingredient150.00 28.6
acid
Silicated mycrocrystallineNF Glidant/Diluent210.53 40.1
cellulose
Dibasic calcium phosphateUSP Filler 95.69 18.2
HydroxypropylmethylcelluloseUSP Drug Release
(HPMC) Modifier 52.50 10.0
Starch~ 1500 NF Binder/Desintegrant8.33 1.6
Stearic acid powder NF Lubricant 5.25 1.0
Magnesium stearate NF Lubricant 2.70 0.5
Weight: 525.00 100.0
Coating**: -
Opadry~ II White MS* Subcoat- 10.50 2.0
Acryleze~ MS* Enteric Coat 52.50 10.0
Opadry~ II White MS* Topcoat 10.50 2.0
Total Weight: ~ ~_ _ _ 598.50 114.0
*MS: Manufacturer's Standard, NF: National Formulary; USP: United States
Pharmacopoeia.
** Several processing steps involved the evaporation of purified water
Pharmacokinetics Analysis
In the following examples and elsewhere herein, terms are as defined below.
The
pharmacokinetic parameters were derived by non-compartmental analysis using
WinNonlin
Version 2.1.
CmaX - the maximum observed plasma concentration.
Tax - the time of occurrence of C",~X.
AUCo_~ - the area under the plasma concentration versus time curve from time
zero to
the last sampling time at which concentrations were at or above the limit of
quantification, calculated by the linear trapezoidal rule.
AUC~- the area under the plasma concentrations versus time curve from time
zero to
infinity, calculated from AUCo_~ + (Cias~/~), where C~as, is the last observed
quantifiable concentration and 7vz is the apparent terminal rate constant.
tl,~ - the apparent terminal half-life, calculated from 1 n 27~.
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Example 7
The pharmacokinetic profile and the effect of food on single rising oral doses
of 3-
APS free acid (modified-release enteric-coated tablet, as described in Table 3
above,
hereinafter "NC-758") in healthy male young (18-45 years) volunteers was
determined. The
S pharmacokinetics of a single oral dose of NC-758 was also determined in a
group of healthy
male elderly (>_ 55 years old) volunteers. The test was a randomized, double-
blind, placebo-
controlled study to assess the pharmacokinetic profile of 4 single rising oral
doses of NC-758
in healthy young (18-45 years) male subjects. Blood samples were collected
during 24 h
following dosing. Plasma concentrations of 3-APS were determined using a
validated LC-
MS/MS method. Results are shown in Table 9.
Table 9 Pharmacokinetic Parameters of 3-APS following Single Oral
Administration of 100, 200, 300 and 400 mg to Young Male Subjects and 200 mg
to
Elderly Male Subjects (Fasted state)
DOSe C",ex Crnex T""x AUCo-T~sst AUC
Ranges
(ng/mL) (ng~mL) (h) (ng~h/mL) (ng~hlmL)
Young (18-45 years)
100 mg 410 Min 276 5 1392 1421
(n=5) Max 629 (5-5) (567 - 2293)(584
- 2314)
200 mg 661 Min 289 5 2898 2492
Max 979 (3-5) (1342 - 4214)(1375
- 3677)
300 mg 904 Min 666 5 3999 4464
(n~) Max 1220 (5-6) (2621 - 5130)(3826
- 5331
400 mg 5367 Min 3630 2 15966
Max 7300 NC
(n=4) (1.5-5)(14153 -
18264)
Elderly (> 55 years)
200 mg Min 871 5 4882 575'78
1094 Max 1250
(n=6) (5-6) (3370 - 6573)
Values are the mean except for T",a, which is the median; Min/Max values for
Cmax are those observed for individuals; and for
1$ AUC and Tmax, where available, minimum and maximum for individuals are in
parentheses
'Parameters derived only for subjects for whom the elimination rate constant
could be estimated; NC: Not calculated
a Calculated for one individual only.
Example 8
The pharmacokinetic profile of multiple rising oral doses of 3-APS free acid
(NC-758
of Table 3 above) in healthy male young subjects (18-45 years) and healthy
male and female
elderly (>_ 55 years) subjects was assessed. The pharmacokinetic profile of a
titrated multiple
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oral rising dose regimen of NC-758 was also assessed in one group of healthy
male young
(18-45 years) subjects. Finally, the pharmacokinetics of a single dose of NC-
758
administered in two different oral formulations (modified-release enteric-
coated vs.
immediate-release uncoated tablet) was compared in one group of healthy male
and female
elderly (>_ 55 years) subjects. Part I was a randomized, double-blind, placebo-
controlled study
to assess the pharmacokinetic profile of 2 multiple rising oral doses of NC-
758 in healthy
young (18-45 years) male subjects. Part II was a randomized, single-blind, two-
period
crossover study to compare the pharmacokinetic profile of a single dose of 3-
APS
administered in two different oral formulations, one being the enteric-coated
NC-758 of Table
3 above and the other being an uncoated formulation, in healthy male and
female elderly (>_
55 years) subjects. In Part I, blood samples were collected through 24 h after
the first dose on
Day 1, before each morning dose on Days 2 to 1 l, and through 48 h after the
final dose on
Day 12. The results are shown in Table 10. For Part II, blood samples were
collected
through 36 and 48 h, respectively. Plasma concentrations of 3-APS were
determined using a
validated LC-MS/MS method. The results are shown in Table 11.
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Table Part I (Escalating
Dose) - Pharmacollsnetic
Parameters of 3-APS
following 100 and 200 Young Male
Single mg to
and Repeated
Oral
Administration
of
Subjects 200 mg to Elderly
and Male and Female Subjects
(Fasted state)
C",.x Ranges Tmax AUCo-t2n AUCm*
Dose
(n9~mL)
(ng/mL) (h) (ngh/mL) (ngh/mL)
Young
(18-45
years)
Day 1
100 mg Min 148 6 1326 1017
BID
282
(n-_6) Max 419 (3-8) (793 - 1964)(828 - 1207)
200 mg Min 355 4 2865 3206
BID
517
(n-6) Max 733 (2.5-8)(1306 - 4644)(2136 -
4275)
Day 12
100 mg Min 141 2.5 1434
BID
256 NC
(n-6) Max 445 (0-6) (865 - 1967)
200 mg Min 284 4 4152
BID
581 NC
(n=5) Max 974 (2.5-6)(1801 - 7980)
Elderly (> 55 years)
Day 1
200 mg BID Min 393 6 5020 5503
897
(n=6) Max 1976 (2-6) (2250 - 9282) (2509 - 9731 )
Day 12
200 mg BID Min 561 5 6287
880 NC
(n-6) Max 1193 (0.5-6) (3630 - 10505)
Values are the mean except for T",a,~ which is the median; Min/Max values for
Cmax are those observed for individuals; and for
AUC and Tmax, where available, minimum and maximum for individuals are in
parentheses
': Parameters derived only in subjects for whom the elimination rate constant
could be estimated
(-): No range since n=1; NC: Not calculated
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Table 11 Part 11 (Crossover Formulation Effect) - Pharmacol;snetic Parameters
of 3-
APS following Single Oral Administration of 100 mg as Enteric-Coated or
Uncoated
Formulation to Elderly Male Subjects (Fasted state)
Cmsx C"'°x Tmax AUCp.Tiest AUC
Formulation Ranges
(nglmL) (ng/mL) (h) (ng~h/mL) (ng~h/mL)
Enteric-Coated 516 Min 166 5 2197 2114
(n = 4) Max 806 (4-5) (709 - 3434) (747 - 3482)
Uncoated Min 546 2 2770 2819
770
(n = 2) Max 994 (2-2) (2254 - 3286) (2284 - 3354)
Values are the mean except for Tms~ which is the median; Min/Max values for
Cmax are those observed for individuals; and for
AUC and Tmax, where available, minimum and maximum for individuals are in
parentheses
'Parameters derived only for subjects for whom the elimination rate constant
could be estimated
Example 9
The pharmacokinetic profile and the effect of food on single oral doses of 3-
APS free
acid (modified-release enteric-coated tablet as described in Table 5 above,
hereinafter "NC-
758-1 ") in healthy male and female elderly (>_ 55 years) volunteers. The test
was an open
label, three-period crossover study to assess the pharmacokinetic profile of 3
single oral doses
of NC-758-1 in healthy elderly (>_ 55 years) male and female subjects. The
blood samples
were collected during 24 h following dosing. Plasma concentrations of 3-APS
were
determined using a validated LC-MS/MS method. The results are shown in Table
12.
Table 12 Pharmacokinetic Parameters of 3-APS following Single
Oral
Administration of 50,100 and 150 mg to Elderly Male
and Female
Subjects (Fasted state)
Cmax C""' T""x AUCo-t AUCm
Dose Ranges
(nglmL) (ng/mL) (h) (ngh/mL) (ngh/mL)
50 mg 469 Min 222 5 1537 1566
(n = 9) Max 842 (5-6) (659 - 2445) (694 - 2473)
100 mg 745 Min 442 5 3128 2871
(n = 9) Max 1182 (3-5) (1338 - 5493) (1362 - 4289)
150 mg 1029 Min 477 5 5303 4497
(n = 8) Max 1434 (4-10) (2450 - 8525) (2477 - 5530)
Values are
the mean
except
for T",a"
which is
the median;
Min/Max
values
for Cmax
are those
observed
for individuals;
and for
AUC and where available, minimum and maximum for individuals
Tmax, are in parentheses
'Parameters
derived
only for
subjects
for whom
the elimination
rate constant
could be
estimated
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Example 10
A multicenter, randomized, double-blind, placebo-controlled and parallel
designed
study has been completed with NC-758-1 from Table 5 above in patients
suffering from mild
to moderate Alzheimer's Disease (AD). This study included assessing the
pharmacokinetic/pharmacodynamic profile in AD patients.
A total of fifty-eight (58) mild to moderate AD patients (MMSE scores = 13 to
26)
were enrolled from 6 centers in the United States. Patients were randomized to
receive in
1:1:1:1 ratio of NC-758-1 at 50, 10, 150 mg B1D or placebo B)D for 12 weeks.
Study
medication was administered orally (tablet). Each patient was evaluated on 6
occasions at
screening, baseline (Week 0], weeks 2, 4, 8 and 12. Blood samples were
collected from each
patient prior to dosing and at specified time points through 12 h post-dose
after the first dose
(Week 0) and the last dose (Week 12). Blood samples were also collected prior
to the first
dose of the day during Week 2, 4 and 8 visits. See Table 13.
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Table 13 Pharmacokinetic Parameters of 3-APS after Single (Week 0) or Repeated
(Week 12) Oral Administration of AlzhemedTM to AD Patients during 12 Weeks
~%max Tmax AVCat A<)C~**
Dose
(ng/mL) (h) (ng~h/mL) (ng~h/mL)
Week 0
50 mg BID 310 6 1321 1396
(n=15) (27 - 776)(2-9) (126 - (157 - 4311 )
4259)
100 mg BID 618 4.7 2467 2569
(n=16) (220 - (2-8) (829 - (861 - 5385)
1666) 5123)
150 mg BID 624 6 2792 3418
(n=14) (14 - 1875)(2-12)(75 - 9042)(670 - 9627)
Week 12
50 mg BID 451 3 1975
NC
(n=15) (77 - 1150)(0-9) (311 -
5421 )
100 mg BID 538 3.5 2590
NC
(n=14) (83 - 901 (0-8) (638 -
) 4711 )
3570
150 mg BID 639 3
(1586 - NC
(n=11 ) (413 - (o-9)
1130)
7432)
Values are the mean except for T",~ which is the median; Minimum and Maximum
values for Cmax, AUCs and Tmax are
provided in the parentheses and are those observed for individuals, where
available;
' or AUCss for Week 12
': Parameters derived only in patients for whom the elimination rate constant
could be estimated
NC: Not calculated
Example 11
The patients from the clinical studies in Example 10 were offered NC-758-1 at
150
mg B)D for an additional 17 months (thus, 20 months total) in an open-label
study. Nineteen
mild to moderate AD patients completed the study. Psychometric tests (ADAS-
cog) were
performed at each visit, that is every 3 months for the first 9 months and
every 4 months for
the last 12 months. Overall, approximately 70% of the mild AD patients had
stabilized or
improved cognitive function tests after 20 months. The mild to moderate
patients (n=19)
showed an average ADAS-cog score of +6.2 points, as opposed to +11.9 points on
average in
comparable historical controls with AD. A subset of mild AD patients (n=10)
responded best
and showed a change from baseline in their average ADAS-cog score of +2.4
points, which
compares favorably with a score of +8.6 points on average in comparable
historical controls.
In addition, the average CDR-BS score in the mild-to-moderate AD patients
after 20 months
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total on the study medication showed +2.7 points on average. This compared
favorably with
the reported 12-month mean change of +2.2 in comparable patients.
In additional tests, it was observed that the drug crossed the bloodJbrain
barrier,
reduced baseline CSF A(i42 (see Figure 1), and reduced the ratio of
A(342/A(3ao (see Figures 2,
3 and 4).
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