Note: Descriptions are shown in the official language in which they were submitted.
2 ~ 9
USE OF ALDOSE REDUCTASE INHIBITORS TO
ENHANCE INSULIN SENSITIVITY IN DIABETES MELLITUS
~_c~round of the Invention
The present invention relates to the field of d~abetes mellitus
therapy. More particularly, this invention relates to the use of com-
pounds having aldose reductase inhibiting activity (herein~fter
reterre~ to as "aldose reductase inhibitors") to correct an abnormal
metabolic pathw~y associated with diabetes mellitus~ thereby enhancing
- and/or restoring insulin sensitivity.
The term "diabetes mellitus" is used to describe chronlc
hyperglycemia and the side effects of glucose toxiclty. There are two
general classifications oF diabetes mellitus: (1) insulin-dependent
(Type I), and (2) noninsulin-dependent (Type II). The present inven-
tion is directed to the treatment of both Type I and Type II diabetes
mellitus, partlcularly Type II.
The above-ci~ed classifications of diabetes mellitus are based on
the role insulin plays in the disease state~ Type I diabetes mellitus
is generally attributable to an insulin deficiency. In contrast, i~ is
clear that simple insulin deficiency cannot entirely account for the
diabetic syndrome seen in Type II diabetes mellitus. This conclusion
is supported by the following observations: (1) in many Type II dia-
betics, insulin deficiency is not present; and (2) even in Type IIdiabetics who have impaired insulin secretion leading to an insulin
deficiency, ~nsulin resistance can be demonstrated to be responsible
for their hyperglycemic state. Reference ~s made to the following
articles fcr further background in this regard: Reaven et al.,
"Honketotic diabetes mellitus: insulin deficiency or insulin resist-
ance?", American Jo_ nal of Medicine, Vol. 60, page 80 ~1976); Alford
et al., "The significance and.interpretation of mildly abnormal oral
glucose tolerance," Oiabetologia/ VolO 7, page 173 (1971); and DeFronzo
et al., "Insulin sensitivity and insulin binding to monocytes in
maturity-onset diabetes," Journal of Clinical Investigation, Vol. 63,
page 939 (1979~.
~g
~ 3 ~
It ls known that the insulin resistance associated with Type II
diabetes mellitus patlents and consequent hyperglycemia can be par-
tially reversed with frequent insulin injections. Moreover, it is
known that insulin receptor function in Type II diabetes mellitus
patients can be modifled by sustained, rigorous caloric and/or carbohy-
drate restriction, oral hypoglycemic drug therapy, insulin injections,
and/or physical exercise which results in weight loss. With these
therapeutic approaches, taken either alone or in combination (i.e.,
diet, exercise, insulin, and/or oral hypoglycemics), the net overall
effect is to lower blood glucose over a sustained time. This effect is
called "induced hypoglycemia." The following articles may be referred
to for further background in connection with known therapeutic methods
of inducing hypoglycemia, and the resulting modiflcation of insulin
receptor function: Savag et al., "Diet induced improvement of abnor-
malities in insulin and glucagon secretion and in insulln receptor
binding in diabetes mellitus," Diabetes Care, Vol. 5, pages 999-1007
(1979); Beck-Nielsen et al., "Normalization oF the insulin sensitivity
and the cellular insulin binding during treatment of obese patients
following treatment with glibenclamide," Acta Endocrinolo~y1 Vol. 90,
pages 103-112 (1979); Beck-Nielsen et al., "Increased insulin sensi-
tivity and cellular insulin binding in obese diabetes following treat-
ment with glibenclamide," Acta Endocrinolo~y~ Vol. 90, pages 451-462
(1979); Rizkalla et al., "Insulin receptor changes in Type II diabetes
after short-term insulin treatment," Horm. Metabol. Res., Vol. 17,
pages 512-517 (1985); Scarlett et al., "Insulin treatment reverses the
insulin resistance of Type II diabetes mellitus," Diabetes Care,
Vol. 5, pages 353-363 (1982~; and Selig, "Hypoglycemia during prolonged
exercise in nor~al men," Endocrinoloqy, Vol. 1g83, pages 209-212 (1~83).
While applicant is not bound by any theory, it is believed that
inducing hypoglycemia will, in tlme, increase insulin sensitivity in
Type II diabetes mellitus. It Follows that frequent episodes of hyper-
glycemia in adults induced, for example, by a high calorie diet and
lack of exercise, will eventually diminish insulin sensitivity and
induce Type Il diabetes mellitus. The aforementioned chronic process
m~y be described as an insidious change in the glucose "set point"
~L 3 ~ 9
--3--
induced by improper life style and aging. The biochemical mechanism
underlylng a loss of insulin sens~tivity and concomitant changes in
glucose metabolism in connection w;th Type II d~abetes mellitus is
believed to involve the energetically expensive enzymatic conversion of
the aldose sugar, glucose, to sorbitol at the cost of NADPH. This loss
of NADPH co-factor substantially suppresses the very dynamic reduction
of oxid~zed glutathione into reduced glutathione. Reduced glutathione
is believed to be involved in maintaining normal insulin receptor func-
tion at the target cells.
~t has been previously demonstrated that insulin release in
response to glucose is related to the redox state of islet cell thiols,
and that reduced glutathione enhances the capacity of glucose to induce
insulin release. See Hallman et al., "Stimul~tlon of insulin release
by thiols," Biochem. Biophys. Acta, Vol. 392, pages 101-109 (1975); and
Ammon et al., "Cysteine analogues potentiate glucose-induced insulin
release in vitro," Diabetes, Vol. 35, pages 1390-1396 (1986), respec-
tively. It has also been suggested that metabolic changes in cellular
glutathione in diabetes mellitus cause other reverslble thiol-disulfide
regulated metabolic changes which result in a net increase in cellular
gluconeogenesis. See Zlegler, "Role of reversible oxidatlon-reduction
of enzyme thiol-disulfide in metabolic regulation," Annu. Rev.
Biochem., Vol. 54, pages 305-329 (1984).
Summary of the Invention
The present invention is directed to enhancing insulin sensitivity
at or within target tissues by administering one or more aldose reduc-
tase inhibitors to patients who are either afflicted with diabetes
mellitus or predisposed to acquiring this disease. An appropriate
aldose reductase inhibitor regimen will prevent and/or reverse loss of
insulin sensitivity. This treatment with aldose reductase inhibitors
results in a gradual decrease ;n insulin resistance by enhancing normal
insulin receptor function at the target cells. This positive effect on
insulin receptor function is believed to be the result of normalization
of the redox state of the affected cells (i.e., normalization of the
~ 3 ~ 9
--4--
conversion of intracellular ox~dized glutath~one to reduced
glutathione); more specifically, the enhancement of insulin receptor
sensit~vlty is believed to result directly from increased cellular
levels of reduced glutathione.
s While applicant is not bound by any theory, it is believed that the~
above cited normallzation of glutathlone metabolism is the indirect
result of interrupt~on of an abnormal metabolic pathway by aldose
reductase inhibitors. More particularly, dlabel:es mellitus is believed
to involve an abnormal metabolic pathway wherein the aldose sugar,
glucose, is converted to sorbitol at the expense of NA~PH. This loss
of NADPH affects the cellular redox state in a manner such that the
conversion of oxidized glutathione to reduced glutathione is decreased,
thereby decreasing the amount of reduced glutathione available at the
insulin receptors. Reduced glutathione either directly or indirectly
(e.g., via a transferase) maintains the insulin receptor in a reduced
thiol state. An insulin receptor active site must be in a reduced
thiol state in order for a mixed disulfide bond or an activated complex
to form between insulin and the insulin receptor. Aldose reductase
inhibitors prevent the above-described depletion of NADPH and resulting
20 decrease in cellular reduced glutathione levels and thiol reduction
potential by inhiblting glucose reducing enzymes, such as aldose reduc-
tase and L-hexonate dehydrogenase, and thereby promote the binding of
both endogenous and exogenous insulin to insul;n receptor sites.
The methods of the present invention are applicable to treatment of
25 both Type I and Type II diabetes mellitus, and to reversal and preven-
tion of Type II diabetes mellitus, and comprise administering a thera-
peutically effective amount of an aldose reductase inhibitor. The
administr tion of an appropriate aldose reductase inhibitor regimen
effectively lowers blood glucose levels in Type I and Type II diabetes
mellitus patients by enhancing the action of endogenous and exogenous
insulin. As the result of the administration of an appropriate aldose
reductase lnhibitor regimen to a patient afflicted with Type I diabetes
mellitus, the amount of insulin required to maintain a normal blood
-5~ 3~fi~
glucose level may be reduced. A similar result w~ll be expected in
Type II diabetes mellitus patients who are receiving insul~n therapy.
In Type II patients receiving a combination of insulin and an aldose
reductase inhibltor9 it may be possible to dlscontinue ;nsulin use
after a relat~vely short course of therapy (e.~., several weeks) with
thls comblnat~on, and to maintain a normal blood glucose level
thereafter using only aldose reductase inhib~tor therapy.
The present invention also provides a method of preventing, or at
least retarding, the onset of Type II diabetes mellitus in patients who
are predisposed to acquiring this disease. A fasting blood glucose
level of greater than 140 mg of glucose per deciliter of blood is gen-
erally associated with a clinical diagnosis of Type II diabetes melli-
tus. In contrast, a patient having a fasting blood glucose level of
greater than 100 mg per deciliter of blood but less than 140 mg per
deciliter is considered to be ~hyperglycemic.~ There is a further
class of patients ~ho are not yet diabetic in a clinical sense, but are
predisposed to acqu;ring diabetes. These patients are referred to as
"latent" or "chemical~ diabetics. In accordance with the present
invention, it is possible to retard the progression of the underlying
disease state in both patients who are hyperglycemic and patients who
may be ident;fied as latent or chem~cal diabetics, thereby preventing
the progression of the disease state to a point at which the patients
would ~e clinlcally diagnosed as having Type II diabetes mellitus.
This prevention or prophylaxis is achieved by enhancing the action of
endogenous insulin, as explained above.
Detailed Description of the Invention
The aldose dose reductase inhibitors which may be employed in the
present lnvention comprise any compound having aldose reductase inhib-
iting activity which is therapeutically effective in enhancing insulin
sensitivity 9 and is safe for use ;n humans and other mammals. Aldose
reductase ;nh~bitors which are particularly suitable for use in the
method of the present invention are disclosed in commonly assigned U.S.
Pdtent Nos. 4,537,892; 4,436,745; and 4,438,272~ The follow;ng patents
disclose additional examples of aldose reductase inhibitors which may
be used in the present invention: U.S. Patent Nos. 3,821,383;
13~12~9
4,117,230- 4,130,714; and 4,181,728. The following
compounds represent particularly preferred aldose
reductase inhibitors:
d.
HN
0~
7,9-difluoro-2-methylspiro(5H-indeno [1,2-b]pyridin-5,3'-pYrolicline)-
2',5'-dione;
O
~N~
00~ ~ NH
1 0
:: ~ N
F
.
7,9-difluoro-2-methylspjro(~H-indeno [l~2-blpyridin-5~4~im~dazolidine)
: ~ 2',5'-dione;
:
~;
~3~2~
--7--
o
HN ~
o ~ NH
F ~ F
a~
~.~
2,7-difluoro-4-methylspiro(9H-fluoren-g~4'-imidazolidine~-2',5'cl10ne:
d.
o
I IN~
05=<~ NH
F~
~: 7-fluoro-2-methylspiro~5H-indeno[1,2-b]-pyridin-5,4'imidazolidine)-
2',5'-dione
:~ :
:: : :
-8- ~31~2~
HN ~
o ~ NH
F ~ F
SCH3
:: .
2,7-difluoro-4-methylthiospiro(9H-fluoren-9,4'-imidazolidine)-2',5'-
dione;
f.
HN~
0~ NH
F_~
F SCH3
7s9-difluoro-2-methylthiospiro(5H-ideno [1,2-b]pyridin-5,4'-
imidazolidine)-2',5'-dione;
-9~
9-
HNt
ol NH
F; ~ F
CH~ F
2,5,7-trifluoro-4-methylspiro(9H-fluoren-9,4'-imidazolidine~-2',5'-
dione;
h.
HN~
O~NH
F~F
SCH3 F
~ .
2,5,7-trifluoro-4-methylthiospiro(9~-fluoren-9,4'-imidazolidine~-Z',5'-
dione:
'
-10- ~ 3~
HN~
0~ ~
H3C ~
\S~
7-methylthiospiro(5H-ideno[1,2-b]pyr~din-5~3'-pyrolidine)-2',5'-dione;
i- ,
: o
HN~
o=51~X NH
F~ F
2,7-difluorospiro~9H-fluoren-9,4'1midazolidin)-2',5'-dione;
:
:
'
1 3 ~
k.
HN~
0~0
F_~. F
2,7-d~fluorospiro~9H-fluoren-9,5'-oxazolidine)-2'5'dione;
o~
F--~--F
~ 297-difluorospiro(9H-fluoren-g,3'-pyrolidine)-2'95'-dione;
.
-12- ~ 3~2~
m.
HN~
~ h~
(S)-6-fluorosplro[chro~an-4,4'-l~idazolidine]-2',5'dione (also called
"SORBINIL~");
5 n. o
~ OH
S ~ N ~
~C~O~
Cf3
N-[~5-(trifluoromethyl~-6-methoxy-1-naphthalenyl]thioxomethyl]-n-
methylglycine (~lso ca led "toLREsTAT~ tnd
,
'
--1 3--
11
o.f~ols
~N
l l I
N~
O ~ F
Br
[3-(4-bromo-2-fluorobenzyl)-4-oxo-3H phthalazin-1-yl]acet~c acid (also
called "STATIL0").
In accordance with the present invention, pat~ents affltcted with
diabetes mellitus and patients predlsposed to acquiring d~abetes melli-
tus are treated with one or more aldose reductase inhibltors in an
amount effecti~e to enhance insulin sensitivity (i.e.~ a "therapeu-
tically effective" amount). The aldose reductase inhibitor(s) may be
administered to the patient by means of a variety of dosage~forms and
routes of administration, as will be readily appreciated by those
skilled in the art. Oral administration is generally preferred, but
- topical admin1stration and administration by injection may be found
preferable in some instances. Dosage regimens (i.e., amount and
frequency) will be determined by the clinician based on factors such as
the patient's physical condition and the duration of action of the
pharmaceutlcal co~posltion employed.
'
