U.S. patent application number 11/784436 was filed with the patent office on 2007-08-09 for novel ppar ligands that do not cause fluid retention, edema or congestive heart failure.
This patent application is currently assigned to Bethesda Pharmaceuticals, Inc.. Invention is credited to Harrihar A. Pershadsingh.
Application Number | 20070185070 11/784436 |
Document ID | / |
Family ID | 31721501 |
Filed Date | 2007-08-09 |
United States Patent
Application |
20070185070 |
Kind Code |
A1 |
Pershadsingh; Harrihar A. |
August 9, 2007 |
Novel PPAR ligands that do not cause fluid retention, edema or
congestive heart failure
Abstract
Methods are provided for treating or prophylactically preventing
metabolic disorders in humans without causing, promoting, or
aggravating fluid retention, peripheral edema, pulmonary edema, or
congestive heart failure, by administration of a therapeutically
effective amount of a compound sufficient to partially or fully
activate peroxisome proliferator activated receptors (PPARs) and
partially or fully inhibit, antagonize or block the activity of
angiotensin II type 1 receptors. Metabolic disorders that can be
treated or prevented include but are not limited to type 2
diabetes, the metabolic syndrome, prediabetes, and other insulin
resistance syndromes. Compounds are provided that antagonize or
block the angiotensin II type 1 (AT1) receptor, function as partial
or full activators of peroxisome proliferator activated receptors
(PPARs), can be used to treat or prevent diseases known to be
treatable or preventable by PPAR activators and were not previously
recognized to be therapeutic targets for angiotensin II receptor
antagonists.
Inventors: |
Pershadsingh; Harrihar A.;
(Bakersfield, CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Assignee: |
Bethesda Pharmaceuticals,
Inc.
Mill Valley
CA
|
Family ID: |
31721501 |
Appl. No.: |
11/784436 |
Filed: |
April 6, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10627372 |
Jul 24, 2003 |
7232828 |
|
|
11784436 |
Apr 6, 2007 |
|
|
|
60402425 |
Aug 10, 2002 |
|
|
|
60455211 |
Mar 15, 2003 |
|
|
|
Current U.S.
Class: |
514/183 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
7/02 20180101; A61P 29/00 20180101; A61P 3/00 20180101; A61P 9/12
20180101; A61P 5/48 20180101; A61P 9/10 20180101; A61P 43/00
20180101; A61P 3/10 20180101; A61K 31/4184 20130101; A61K 31/415
20130101; A61P 3/04 20180101; A61K 31/41 20130101; A61P 3/06
20180101; A61P 1/16 20180101; A61P 13/12 20180101; A61P 9/04
20180101 |
Class at
Publication: |
514/183 |
International
Class: |
A61K 31/33 20060101
A61K031/33 |
Claims
1-17. (canceled)
18. A composition for treating hypertension, the composition
comprising: a therapeutically effective amount of a diuretic,
wherein the therapeutically effective amount of the diuretic is
sufficient to increase a risk for hyperglycemia and a
therapeutically effective amount of a compound sufficient to (a) at
least partially activate peroxisome proliferator activated
receptor-gamma (PPAR-.gamma.), (b) at least partially inhibit,
antagonize or block an activity of angiotensin II type 1 receptors
and (c) reduce hyperglycemia.
19. The composition of claim 18, wherein the therapeutically
effective amount of the compound is sufficient to reduce a
condition of dyslipidemia selected from the group consisting of
hyperlipemia, hypercholesterolemia, and hypertriglyceridemia.
20. The composition of claim 18, wherein the therapeutically
effective amount of the compound is sufficient to reduce
hyperinsulinemia.
21. The composition of claim 18, wherein the diuretic is selected
from the group consisting of a thiazide and a
chlorbenzenesulfonamide.
22. The composition of claim 21, wherein the diuretic is a thiazide
and the thiazide is hydrochlorothiazide.
23. The composition of claim 21, wherein the diuretic is a
chlorbenzenesulfonamide and the chlorbenzenesulfonamide is
chlorthalidone.
24. The composition of claim 18, wherein the compound is selected
from the group consisting of telmisartan, irbesartan, losartan,
candesartan, candesartan cilexetil, olmesartan, and olmesartan
medoximil, a tautomeric form thereof, a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable solvate
thereof.
25. The composition of claim 18, wherein the compound is
telmisartan.
26. The composition of claim 25, wherein the diuretic is
hydrochlorothiazide.
27. The composition of claim 25, wherein the diuretic is
chlorthalidone.
28. The composition of claim 18, wherein the compound is
candesartan cilexetil.
29. The composition of claim 28, wherein the diuretic is
hydrochlorothiazide.
30. The composition of claim 18, wherein the composition is
suitable for administration in a pharmaceutically acceptable
formulation.
31. The composition of claim 18, formulated for oral
administration.
32. The composition of claim 31, comprising a solid or a fluid unit
dosage form selected from the group consisting of tablets, hard
gelatin capsules, soft gelatin capsules, suspensions, elixirs, and
syrups.
33. The composition of claim 18, formulated for parenteral
administration.
34. The composition of claim 33 comprising an aqueous solution,
wherein the compound is at a concentration of between about 1 to
about 100 mg/ml.
35. A unit dose comprising the composition of claim 25, containing
a dose of telmisartan suitable for oral administration of
telmisartan to a subject in need thereof, wherein the dose is
between about 0.1 to about 10 mg/kg body weight of the subject.
36. The composition of claim 26, wherein 1 part by weight of
telmisartan is combined with 0.01 to 100 parts by weight of
hydrochlorothiazide.
37. The composition of claim 36, wherein the 1 part by weight of
telmisartan is 80 mg.
38. The composition of claim 36, wherein the 1 part by weight of
telmisartan is 160 mg.
39. A unit dose comprising the composition of claim 36.
40. A unit dose comprising the composition of claim 27 containing a
dose of telmisartan suitable for oral administration of telmisartan
to a subject in need thereof, wherein the dose is between about 0.1
to about 10 mg/kg body weight of the subject.
41. The composition of claim 27, wherein 1 part by weight of
telmisartan is combined with 0.01 to 100 parts by weight of
chlorthalidone.
42. The composition of claim 41, wherein the 1 part by weight of
telmisartan is 80 mg.
43. The composition of claim 41, wherein the 1 part by weight of
telmisartan is 160 mg.
44. A unit dose comprising the composition of claim 41.
45. The composition of claim 29, wherein 1 part by weight of
candesartan cilexetil is combined with 0.01 to 100 parts by weight
of hydrochlorothiazide.
46. A unit dose comprising the composition of claim 45.
47. A method of treating hypertension comprising administering the
composition of claim 18 to a subject in need thereof.
48. The method of claim 47, wherein the hypertension is
insulin-resistant hypertension.
49. A method of treating hypertension comprising administering the
composition of claim 26 to a subject in need thereof.
50. The method of claim 49, wherein the hypertension is
insulin-resistant hypertension.
51. A method of treating hypertension comprising administering the
composition of claim 27 to a subject in need thereof.
52. The method of claim 51, wherein the hypertension is
insulin-resistant hypertension.
53. A method of treating hypertension comprising administering the
composition of claim 29 to a subject in need thereof.
54. The method of claim 53, wherein the hypertension is
insulin-resistant hypertension.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit under 35 U.S.C. .sctn.119(e)
of provisional application U.S. Ser. No. 60/402,425, filed on Aug.
10, 2002, and provisional application U.S. Ser. No. 60/455,211
filed on Mar. 15, 2003, which are herein incorporated by reference
in their entirety for all purposes.
TECHNICAL FIELD OF THE INVENTION
[0002] This invention relates to the field of prevention and
treatment of cardiovascular diseases and insulin resistance
syndromes. Specifically, this invention relates to compounds that
increase both the activity of peroxisome proliferator activated
receptors (PPARs) and blocks/antagonizes activity of the
angiotensin II type 1 receptor. More specifically, this invention
relates to novel clinical uses of certain angiotensin II type 1
receptor blockers (ARBs) which can increase the activity of
peroxisome proliferator activated receptors (PPARs).
BACKGROUND OF THE INVENTION
[0003] Peroxisome proliferator-activated receptors (PPARs) are
members of the nuclear receptor superfamily of ligand-activated
transcription factors. Three subtypes of PPARs have been cloned
from the mouse and human: i.e., PPAR.alpha., PPAR.gamma., and
PPAR.delta.. The PPARs are important regulators of carbohydrate and
lipid metabolism, cell growth and differentiation, phenotype
transition, apoptosis, neovascularization, immunoregulation and the
inflammatory response. Compounds that activate PPARs are useful for
the treatment and prevention of a variety of clinical disorders
including but not limited to the metabolic syndrome, obesity,
pre-diabetes, type 2 diabetes, and other insulin resistant
syndromes, hypertension, atherosclerosis, dyslipidemia,
inflammatory skin diseases such as psoriasis, inflammatory bowel
disease, and inflammatory neurodegenerative diseases such as
multiple sclerosis and Alzheimer's disease. The metabolic syndrome
as referred to herein includes the metabolic syndrome as defined by
either the World Health Organization (WHO) or the National
Cholesterol Education Program (NCEP) (Zimmet P, et al. Global and
societal implications of the diabetes epidemic. Nature. (2001)
414:782-7; Alberti K G, Zimmet P Z. Definition, diagnosis and
classification of diabetes mellitus and its complications. Part 1:
diagnosis and classification of diabetes mellitus provisional
report of a WHO consultation. Diabet Med. (1998) 15:539-53;
Executive Summary of The Third Report of The National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, And
Treatment of High Blood Cholesterol In Adults (Adult Treatment
Panel III). JAMA (2001) 285:2486-97.).
[0004] Examples of known compounds that can activate PPARs include
thiazolidinediones (e.g. rosiglitazone, pioglitazone MK 767
(KRP-297), MCC-555, netoglitazone, balaglitazone, rivoglitazone)
that primarily activate PPARgamma or PPARgamma and PPARalpha, and
non-thiazolidinediones that can activate any combination of
PPARgamma, PPARalpha and PPARdelta (e.g. JTT-501, LSN862, DRF 4832,
LM 4156, LY 510929, LY 519818, TY 51501, X 334), certain
tyrosine-based derivatives (e.g. GW1929, GW7845), phenylacetic
acid-based derivatives, phenoxazine phenyl propanoic acid
derivatives (e.g. DRF 2725, DRF 2189), cinammic and dihydrocinammic
acid-based derivatives (e.g. tesaglitazar (AZ 242)), and
3-Phenyl-7-propylbenzisoxazoles (Adams A D, et al. Bioorg Med Chem
Lett. (2003) 13:931-5), that can activate PPARgamma in combination
with PPARalpha or PPARdelta or both PPARalpha and PPARdelta.
Although compounds are available that may primarily activate
PPARalpha alone or PPARdelta alone, it is common for such compounds
to also cause at least some degree of PPARgamma activation as
well.
[0005] Although drugs that activate PPARgamma have proven to be
valuable for the prevention and treatment of type 2 diabetes and a
variety of other disorders, the currently available agents cause
adverse effects or aggravate certain conditions that can limit the
clinical utility and safety of these ligands. Some of the principle
limiting side effects or conditions that can be provoked or
aggravated by both thiazolidinedione and non-thiazolidinedione
compounds that activate PPARgamma either alone or in combination
with other PPARs are fluid retention, peripheral edema, pulmonary
edema, and congestive heart failure. Both rosiglitazone and
pioglitazone have received regulatory approval for the treatment of
type 2 diabetes in many countries including the United States and
throughout the European Community. The extensive accumulated
experience with worldwide use of these drugs has revealed that
thiazolidinediones can cause fluid retentions which exacerbates or
leads to edema and/or congestive heart failure (CHF). Patients with
ongoing edema are prone to adverse effects when on
thiazolidinedione therapy, and especially if this is combined with
administration with insulin, consisting of up to 16% of patients in
the latter group. This is potentially a serious problem,
considering that among patients with type 2 diabetes likely to be
treated with thiazolidinediones or other non-thiazolidinedione
agonist, a significant percentage have CHF or are at high risk for
developing CHF because of their high cardiovascular risk profiles.
Fluid retention caused by PPAR activators can not only cause volume
expansion and peripheral edema, but also can also induce or
aggravate life-threatening conditions such as CHF and pulmonary
edema. Therefore, there is considerable interest in identifying and
using PPARgamma activators that do not cause substantial fluid
retention and therefore do not increase the risk for edema and
congestive heart failure.
[0006] The current invention relates to the surprising discovery
that certain ARBs can increase the activity of PPARgamma and can be
used to treat or prevent type 2 diabetes, the metabolic syndrome,
and other disorders responsive to PPAR activators or PPAR
activation, without increasing the risk for fluid retention,
peripheral edema, pulmonary edema, or congestive heart failure.
Although previous studies have shown that the risk for type 2
diabetes in patients given ARBs is lower than that in patients
given other antihypertensive drugs, it could not have been
predicted that certain ARBs could be used to prevent or treat type
2 diabetes, the metabolic syndrome or other disorders responsive to
PPAR ligands.
[0007] It has been unclear whether ARBs actually decreased the risk
for diabetes or whether the drugs to which they were being compared
increased the risk for diabetes. For example, the lower risk of
diabetes reported in patients given ARBs versus beta blockers or
thiazide diuretics was due to the fact that beta blockers and
thiazide diuretics aggravate insulin resistance and therefore, the
results of clinical studies comparing ARBs to other agents cannot
be used to predict whether ARBs can be used to prevent or treat
diabetes or other disorders responsive to PPARgamma activators.
[0008] Several trials have investigated the effects of ARBs on
glucose homeostasis but the results are conflicting and
controversial (for a review of this subject, see: Bernobich E, et
al. Drugs (2002) 62:1295-1314). There are no data available that
consistently demonstrate that ARBs improve insulin sensitivity,
attenuate insulin resistance, or can be used to treat or prevent
type 2 diabetes, the metabolic syndrome, or other insulin
resistance syndromes. Expert opinions expressed in the medical and
scientific literature hold that drugs that block angiotensin II
type 1 receptors (ARBs) (also known as "sartans") are
"metabolically neutral" (Epstein M. Angiotensin II Receptor
Antagonists: Current Status. In: Angiotensin II Receptor
Antagonists. Epstein M and Brunner H R (eds), Hanley & Belfus,
Inc., Philadelphia, (2002) pp 257-261). For example, the ARB
losartan has a neutral effect on glucose metabolism, insulin
sensitivity, and serum concentrations in patients with mild
hypertension (Bernobich E, et al. Drugs (2002) 62:1295-1314), and
in clinical studies with diabetic patients, candesartan does not
appreciably alter their hemoglobin Alc, glucose concentration or
lipid profile (Easthope S E, et al. Drugs 2002; 62:1253-87).
[0009] In a recent clinical trial (LIFE trial) where the ARB
losartan was compared to the .beta.-blocker atenolol, the incidence
of new-onset type 2 diabetes was greater in the atenolol treated
patients than in those treated with losartan (Dahlof B, et al.
Lancet (2002) 359:995-1003). However, .beta.-blockers like atenolol
are known to be clinically diabetogenic and can promote or worsen
insulin resistance and thereby promote the development of type 2
diabetes (Teuscher A U, et al. J Hypertens Suppl. (1997)
15:S67-75). Therefore, the lower incidence of new-onset type 2
diabetes in the losartan arm of the study actually reflected an
increase in the incidence of new-onset type 2 diabetes in the
atenolol arm. Studies showing a lower incidence of new onset
diabetes in patients treated with the ARB candesartan compared to
patients treated with thiazide diuretics also indicate that the ARB
candesartan did not decrease the risk for diabetes, rather, the
thiazide diuretic increased the risk for diabetes. Consequently,
the prior art could not be used to predict that losartan,
telmisartan, irbesartan, or any other ARB could be used to prevent
or treat type 2 diabetes, the metabolic syndrome, or other forms of
insulin resistance. Moreover, because the ARBs have important
structural chemical differences, any unusual or unexpected results
obtained with one ARB cannot be used to predict that similar
results would be obtained with another ARB.
[0010] In the obese Zucker rat, Henriksen et al. found that oral
administration of an extremely high dose of irbesartan improved
insulin sensitivity but apparently failed to improve lipid levels
(Henriksen E J, et al. Selective angiotensin II receptor antagonism
reduces insulin resistance in obese Zucker rats. Hypertension.
(2001) 38:884-90). However, the obese Zucker rat is an unusual form
of obesity and insulin resistance that is caused by mutations in
the leptin receptor and furthermore, the rats studied by Henriksen
did not have type 2 diabetes. Mutations in leptin receptors in
humans are extremely rare and almost never account for type 2
diabetes, obesity, insulin resistance, or the metabolic syndrome in
humans. Therefore, the studies by Henriksen et al in which an
extremely high dose of irbesartan was found to improve insulin
sensitivity in obese Zucker rats can not be used to predict or
imply that irbesartan or any other ARB could be used to activate
PPAR.gamma. in vivo or be used to treat or prevent type 2 diabetes,
the metabolic syndrome, or other insulin resistance syndromes in
humans.
[0011] In 2002, after the current discovery was made, Sharma and
colleagues reported that very high concentrations of angiotensin II
can inhibit differentiation of human preadipocytes and that high
concentrations of irbesartan can enhance adipogenesis (Janke J, et
al. Mature adipocytes inhibit in vitro differentiation of human
preadipocytes via angiotensin type 1 receptors. Diabetes. (2002)
51:1699-707). Based on these findings and recent evidence showing
that lack of adipose tissue can promote diabetes by causing excess
storage of fat in muscle, liver, and pancreas (Danforth E, Jr.
Failure of adipocyte differentiation causes type II diabetes
mellitus? Nat. Genet. (2000) 26:13), Sharma and colleagues proposed
that blockade of the renin-angiotensin system per se might prevent
diabetes by promoting the recruitment and differentiation of
adipocytes (Sharma A M, et al. Angiotensin blockade prevents type 2
diabetes by formation of fat cells. Hypertension. (2002)
40:609-11). In the current studies, we have found that moderate
concentrations of telmisartan and higher concentrations of
irbesartan can activate PPAR.gamma. which is known to promote
adipogenesis, however, other ARBs failed to show any effects on
PPAR.gamma. gamma activity or adipogenesis. Thus, blockade of
angiotensin receptors per se is not sufficient to promote increased
PPARgamma activity or adipogenesis and not sufficient to prevent or
treat type 2 diabetes or any other insulin resistance syndrome
including the metabolic syndrome.
[0012] In light of a number of clinical and experimental studies
suggesting that angiotensin converting enzyme (ACE) inhibitors can
improve insulin sensitivity and decrease the incidence of new onset
type 2 diabetes in patients with hypertension, the question again
arises as to whether pharmacological interruption of the
renin-angiotensin system by other means, such as with angiotensin
receptor blockers (ARBs), could also be predicted to be useful for
preventing or treating type 2 diabetes or other insulin resistance
syndromes (Yusuf S, et al. Ramipril and the development of
diabetes. JAMA. 2001; 286:1882-5; Hansson L, et al. Effect of
angiotensin-converting-enzyme inhibition compared with conventional
therapy on cardiovascular morbidity and mortality in hypertension:
the Captopril Prevention Project (CAPPP) randomized trial. Lancet.
(1999) 353:611-6; Major outcomes in high-risk hypertensive patients
randomized to angiotensin-converting enzyme inhibitor or calcium
channel blocker vs diuretic: The Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA. (2002) 288:2981-97; Bemobich E, et al. The role of the
angiotensin system in cardiac glucose homeostasis: therapeutic
implications. Drugs. (2002) 62:1295-314). However, recent studies
have shown that the insulin sensitizing effects of ACE inhibitors
are related to their effects on kinin metabolism rather than their
effects on the renin-angiotensin system (Tomiyama H, et al. Kinins
contribute to the improvement of insulin sensitivity during
treatment with angiotensin converting enzyme inhibitor.
Hypertension. (1994) 23:450-5; Shiuchi T, et al. ACE inhibitor
improves insulin resistance in diabetic mouse via bradykinin and
NO. Hypertension. (2002) 40:329-34; Bernobich E, et al. The role of
the angiotensin system in cardiac glucose homeostasis: therapeutic
implications. Drugs. (2002) 62:1295-314). Thus, based on the
results of studies using ACE inhibitors, it could not have been
predicted that any of the existing ARBs would activate PPAR.gamma.
and be useful for preventing or treating type 2 diabetes, the
metabolic syndrome or any other insulin resistance syndrome.
SUMMARY OF THE INVENTION
[0013] While not wishing to be bound by theory, drugs that activate
PPARgamma can cause fluid retention through a number of mechanisms.
A surprising feature of this invention is that the fluid retention
usually caused by drugs that activate PPARgamma can be prevented or
attenuated by blockade of angiotensin II type 1 receptors. Because
multiple mechanisms may be involved in the fluid retention caused
by PPARgamma ligands, it could not have been predicted that
blockade of angiotensin receptors could prevent or attenuate the
fluid retention caused by PPARgamma ligands in humans. Thus, it
could not have been predicted that ARBs that activate PPAR could be
used to treat or prevent type 2 diabetes, the metabolic syndrome,
or other insulin resistance syndromes without increasing the risk
for fluid retention, edema, or congestive heart failure.
[0014] Until the current discovery described herein, it was not
known that certain ARBs could increase the activity of PPARgamma.
Thus, it could also not have been predicted that certain ARBs could
be used to treat or prevent insulin resistance syndromes, type 2
diabetes, the metabolic syndrome or other conditions known to be
treatable by drugs that increase the activity of PPARgamma.
[0015] The current discovery also provides improved methods for
preventing and treating inflammatory diseases without promoting or
aggravating fluid retention, peripheral edema, pulmonary edema, or
congestive heart failure by administering PPAR activators that also
antagonize the angiotensin II type 1 receptor. Although it has long
been recognized that compounds that activate PPAR or block
angiotensin II type 1 receptors have anti-inflammatory effects, it
could not have been predicted that certain compounds would have the
capacity to both activate PPARs and block angiotensin receptors.
Because such compounds exert anti-inflammatory effects through
multiple pathways (PPAR pathway and the angiotensin receptor
pathway), they provide a superior ability to treat or prevent
inflammatory diseases than PPAR activators or ARBs alone. Such
compounds that activate PPARs and block angiotensin receptors are
also superior to PPAR activators because unlike currently
recognized PPAR activators, the compounds of the current invention
do not promote or aggravate fluid retention, peripheral edema,
pulmonary edema or heart failure.
[0016] The current invention describes the surprising finding that
drugs exist and can be developed that block the angiotensin II Type
1 receptor (angiotensin receptor blockers or ARBs) and can also
increase the activity of PPARgamma. That is, some drugs exist that
can function as both an ARB and as a PPAR activator. Such agents
include, but are not limited to, telmisartan and irbesartan and can
be used to prevent or treat type 2 diabetes, the metabolic
syndrome, insulin resistance, and other disorders responsive to
PPARgamma activation including inflammatory disorders without
causing fluid retention, edema, or congestive heart failure. Thus,
angiotensin receptor blockers such as telmisartan and irbesartan
can be surprisingly used to treat conditions that are known by
those skilled in the art to be responsive to PPARgamma activators
and can do so without causing fluid retention, edema, or congestive
heart failure.
[0017] Because ARBs that increase the activity of PPARgamma do not
cause substantial fluid retention and do not increase the risk for
edema and CHF, they represent a significant improvement over the
currently recognized drugs that increase the activity of PPARgamma.
Specific examples of ARBs that increase the activity of PPARgamma
are provided together with a description of novel clinical uses of
these agents and instructions for such use. This invention also
describes the fact that new ARBs can be developed that also
increase the activity of PPARgamma or PPARgamma and PPARalpha. Such
new ARBs will also be useful for treating or preventing type 2
diabetes, the metabolic syndrome, and other disorders responsive to
administration of drugs that activate PPARs without promoting fluid
retention, peripheral edema, pulmonary edema, or congestive heart
failure.
[0018] Because the compounds of this invention also activate PPARs
in addition to blocking the angiotensin II type 1 receptor, said
compounds provide a more effective means of treating or preventing
inflammatory and metabolic disorders including atherosclerosis than
compounds that block the angiotensin II type 1 receptor but do not
activate PPARs.
[0019] Also surprisingly, by administering an ARB or ACE inhibitor
prior to or concurrently with compounds that activate PPARgamma
either as separate pills or tablets or capsules, or by
administering both drugs formulated in a single pill or tablet or
capsule, one can also prevent or treat glucose intolerance or type
2 diabetes and other PPAR responsive disorders without causing
fluid retention, edema, or congestive heart failure.
[0020] This invention relates to methods for treating or
prophylactically preventing an inflammatory or metabolic disorder
in a mammal (human or non-human) without causing, promoting, or
aggravating fluid retention, peripheral edema, pulmonary edema, or
congestive heart failure, by administering to a mammal in need
thereof, a therapeutically effective amount of a compound
sufficient to partially or fully activate peroxisome proliferator
activated receptors (PPARs) and partially or fully inhibit,
antagonize or block the activity of angiotensin II type 1
receptors.
[0021] In one embodiment the mammal is a human child, adolescent or
adult and the therapeutically effective amount of the compound is
used to prepare a medicament for treatment of the metabolic
disorder in the human.
[0022] In one embodiment, said compound increases the activity of
the PPAR subtype, PPARgamma or the PPARgamma-retinoid X receptor
(PPARgamma-RXR) heterodimer, independently or in combination with
an increase in activity of PPARalpha, PPARdelta, or both PPARalpha
and PPARdelta.
[0023] In one embodiment said compound is administered in a
pharmacologically acceptable form and in a therapeutically
effective amount sufficient to prophylactically prevent, slow,
delay or treat a metabolic disorder or disease selected from the
group consisting of insulin resistance, glucose intolerance,
impaired glucose tolerance, impaired fasting serum glucose,
impaired fasting blood glucose, hyperinsulinemia, pre-diabetes,
type 1 diabetes, type 2 diabetes mellitus, insulin-resistant
hypertension, the metabolic syndrome, the metabolic hypertensive
syndrome, (metabolic) syndrome X, the dysmetabolic syndrome,
obesity, visceral obesity, hypertriglyceridemia, elevated serum
concentrations of free fatty acids, elevated serum concentrations
of C-reactive protein, elevated serum concentrations of
lipoprotein(a), elevated serum concentrations of homocysteine,
elevated serum concentrations of small, dense low-density
lipoprotein (LDL)-cholesterol, elevated serum concentrations of
lipoprotein-associated phospholipase (A2), reduced serum
concentrations of high density lipoprotein (HDL)-cholesterol,
reduced serum concentrations of HDL(2b)-cholesterol, and reduced
serum concentrations of adiponectin.
[0024] In a particular embodiment, as described in U.S. Pat. No.
6,100,252 (Heterocyclic compounds and their use as angiotensin
antagonists by Naka, et al.) the compound is of the general
formula: ##STR1## [wherein R1 is an optionally substituted
hydrocarbon residue which is optionally bonded through a
hetero-atom; R2 is an optionally substituted 5-7 membered
heterocyclic residue having, as a group capable of constituting the
ring, a carbonyl group, a thiocarbonyl group, an optionally
oxidized sulfur atom or a group convertible into them; X is a
direct bond or a spacer having an atomic length of two or less
between the ring Y and the ring W; W and Y are independently an
optionally substituted aromatic-hydrocarbon residue optionally
containing a hetero-atom or an optionally substituted heterocyclic
residue; n is an integer of 1 or 2; a and b forming the
heterocyclic residue are independently one or two optionally
substituted carbon or hetero atoms; c is an optionally substituted
carbon or hetero atom; and, in the group of the formula: ##STR2##
substituents on adjacent two atoms forming the ring are optionally
bonded to each other to form a 5-6 membered ring together with the
two atoms forming the ring] or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate thereof.
[0025] In one embodiment, the compound is formulated for oral
administration. In another embodiment, the compound is formulated
for topical administration.
[0026] In a preferred embodiment, the compound is telmisartan, or
an analog thereof. In another preferred embodiment, the compound is
irbesartan, or an analog thereof. In some embodiments, the total
effective daily orally administered dose is selected from the range
of from about 20 mg to 1000 mg.
[0027] The present invention further provides methods for screening
compounds for treating or prophylactically preventing an
inflammatory or metabolic disorder in a mammal by selecting a
compound having the properties of: (a) at least partially
activating peroxisome proliferator activated receptors (PPARs); and
(b) at least partially inhibiting, antagonizing or blocking an
activity of angiotensin II type 1 receptors. In some embodiments
the method further includes selecting a compound that does not
cause, promote, or aggravate fluid retention, peripheral edema,
pulmonary edema, or congestive heart failure in the mammal.
DETAILED DESCRIPTION OF THE INVENTION
[0028] This invention relates to a method for preventing, delaying
or treating insulin resistance, pre-diabetes, glucose intolerance,
impaired glucose tolerance, the metabolic syndrome, type 2
diabetes, or other insulin resistance syndromes without causing
systemic fluid retention, or increasing the risk for fluid
retention, peripheral edema, pulmonary edema, or congestive heart
failure by administering a compound that increases both the
activity of peroxisome proliferator activated receptors and
blocks/antagonizes activity of the angiotensin II type 1 receptor.
This invention further relates to novel clinical uses of certain
angiotensin II type 1 receptor blockers (ARBs) based on the
discovery that said compounds can increase the activity of
peroxisome proliferator activated receptors (PPARs), PPAR.gamma.,
PPAR.alpha., or PPAR.delta., or any combination thereof, and can be
used to treat and to prevent PPAR-regulated diseases and their
complications including metabolic, inflammatory, proliferative, and
cardiovascular diseases not previously recognized to be therapeutic
targets for ARBs or more effectively than ARBs that do not activate
PPARs. This invention further relates to methods for developing and
using drugs that have the dual ability to block or inhibit activity
of the renin-angiotensin-aldosterone system and to activate PPARs.
Another aspect of this invention relates to methods for screening
libraries of compounds to determine which are likely candidates for
use in the practice of this invention.
Definitions
[0029] Body mass index (BMI) of a human patient is defined as the
weight in kilograms divided by the square of the height in meters,
such that BMI has units of kg/m.sup.2.
[0030] Overweight is defined as the condition wherein the
individual has a BMI greater than or 25 kg/m.sup.2 and less than 30
kg/m.sup.2.
[0031] Obesity is defined as the condition wherein the individual
has a BMI equal to or greater than 30 kg/m.sup.2. In another
aspect, the term obesity is used to mean visceral obesity.
[0032] Visceral obesity is defined as a waist-to-hip ration of 1.0
in men and 0.8 in women, which, in another aspect defines the risk
for insulin resistance and the development of pre-diabetes.
[0033] Euglycemia is defined as the condition in which a subject
has a fasting blood glucose concentration within the normal range,
greater than 70 mg/dl (3.89 mmol/L) and less than 110 mg/dl (6.11
mmol/L). The word fasting has the usual meaning as a medical
term.
[0034] Impaired glucose tolerance (IGT), is defined as the
condition in which a subject has a fasting blood glucose
concentration or fasting serum glucose concentration greater than
110 mg/dl and less than 126 mg/dl (7.00 mmol/L), or a 2 hour
postprandial blood glucose or serum glucose concentration greater
than 140 mg/dl (7.78 mmol/L) and less than 200 mg/dl (11.11
mmol/L). The term impaired glucose tolerance is also intended to
apply to the condition of impaired fasting glucose.
[0035] Hyperinsulinemia is defined as the condition in which a
subject with insulin resistance, with or without euglycemia, in
which the fasting or postprandial serum or plasma insulin
concentration is elevated above that of normal, lean individuals
without insulin resistance, having a waist-to-hip ration<1.0
(for men) or <0.8 (for women).
[0036] The terms "insulin-sensitizing", "insulin
resistance-improving" or "insulin resistance-lowering" are
synonymous and used interchangeably.
[0037] Insulin resistance is defined as a state in which
circulating insulin levels in excess of the normal response to a
glucose load are required to maintain the euglycemic state (Ford E
S, et al. JAMA. (2002) 287:356-9). Insulin resistance, and the
response of a patient with insulin resistance to therapy, may be
quantified by assessing the homeostasis model assessment to insulin
resistance (HOMA-IR) score, a reliable indicator of insulin
resistance (Katsuki A, et al. Diabetes Care 2001; 24:362-5). The
estimate of insulin resistance by the homeostasis assessment model
(HOMA)-IR score is calculated with the formula (Galvin P, et al.
Diabet Med 1992; 9:921-8): HOMA-IR=[fasting serum insulin
(.mu.U/mL)].times.[fasting plasma glucose (mmol/L)/22.5]
[0038] Patients with a predisposition for the development of IGT or
type 2 diabetes are those having euglycemia with hyperinsulinemia
and are by definition, insulin resistant. A typical patient with
insulin resistance is usually overweight or obese.
[0039] The term pre-diabetes is the condition wherein an individual
is pre-disposed to the development of type 2 diabetes. Pre-diabetes
extends the definition of impaired glucose tolerance to include
individuals with a fasting blood glucose within the high normal
range.gtoreq.100 mg/dL (J. B. Meigs, et al. Diabetes 2003;
52:1475-1484) and fasting hyperinsulinemia (elevated plasma insulin
concentration). The scientific and medical basis for identifying
pre-diabetes as a serious health threat is laid out in a Position
Statement entitled "The Prevention or Delay of Type 2 Diabetes"
issued jointly by the American Diabetes Association and the
National Institute of Diabetes and Digestive and Kidney Diseases
(Diabetes Care 2002; 25:742-749).
[0040] Individuals likely to have insulin resistance are those who
have two or more of the following attributes: 1) overweight or
obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more
1.sup.st degree relative with a diagnosis of IGT or type 2
diabetes. Insulin resistance can be confirmed in these individuals
by calculating HOMA-IR score. For the purpose of this invention,
insulin resistance is defined as the clinical condition in which an
individual has a HOMA-IR score>4.0 or a HOMA-IR score above the
upper limit of normal as defined for the laboratory performing the
glucose and insulin assays.
[0041] Type 2 diabetes is defined as the condition in which a
subject has a fasting blood glucose or serum glucose concentration
greater than 125 mg/dl (6.94 mmol/L).
[0042] The metabolic syndrome, also called syndrome X (when used in
the context of a metabolic disorder), also called the dysmetabolic
syndrome is a syndrome complex with the cardinal feature being
insulin resistance (Laaksonen D E, et al. Am J Epidemiol 2002;
156:1070-7). According to the ATP III/NCEP guidelines (Executive
Summary of the Third Report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults (Adult Treatment Panel III)
JAMA: Journal of the American Medical Association (2001)
285:2486-2497), diagnosis of the metabolic syndrome is made when
three or more of the following risk factors are present: [0043] 1.
Abdominal obesity, defined as waist circumference>40 inches or
102 cm in men, and >35 inches or 94 cm in women [0044] 2.
Triglycerides:.gtoreq.150 mg/dL [0045] 3. HDL-cholesterol.ltoreq.40
mg/dL in men [0046] 4. Blood pressure.gtoreq.130/85 mm Hg
(SBP.gtoreq.130 or DBP.gtoreq.85) [0047] 5. Fasting blood
glucose.gtoreq.110 mg/dL
[0048] The NCEP definitions have been validated (Laaksonen D E, et
al. Am J. Epidemiol. (2002) 156:1070-7).
[0049] The term congestive heart failure (CHF) includes heart
failure of any etiology, including but not limited to, heart
failure with diastolic dysfunction, heart failure with systolic
dysfunction, heart failure associated with cardiac hypertrophy, and
heart failure that develops as a result of infectious myocarditis,
inflammatory myocarditis, chemical myocarditis, cardiomyopathy of
any etiology, hypertrophic cardiomyopathy, congenital
cardiomyopathy, and cardiomyopathy associated with ischemic heart
disease or myocardial infarction.
[0050] The term PPAR means one or any combination of PPARalpha,
PPARgamma and PPARdelta.
[0051] The term PPARgamma means one or any combination of
PPARgamma1, PPARgamma2, PPARgamma3.
[0052] The terms PPAR activator or PPARgamma activator means any
compound that, by any mechanism, increases, or causes an increase
in the activity of PPARgamma or the heterodimer of PPARgamma with
the retinoid X receptor (RXR), either by direct binding to either
PPARgamma or RXR or indirectly through any other mechanism that
affects the ability of PPARgamma or the PPARgamma-RXR heterodimer
to influence gene expression. Such PPAR activators may affect
PPARgamma activity either alone or in combination with activation
of other PPARs including either PPARalpha, PPARdelta, or both
PPARalpha and PPAR delta.
[0053] A PPAR-dependent disease is a disease in which 1)
administration of a PPAR ligand slows, ameliorates, stops or
reverses the pathological process, and or 2) said disease is
associated with impaired signal transduction upstream from PPAR and
its interaction with the gene transcription machinery, and or 3)
activation, partial activation or antagonism by a PPAR ligand
(PPAR.alpha., PPAR.gamma., PPAR.delta.) leads to the prevention,
amelioration, cure, or arrest of said disease or pathological
process.
[0054] An angiotensin II-dependent disease is a disease in which:
1) administration of a AT1 receptor antagonist slows, ameliorates,
stops or reverses the pathological process, and or 2) said disease
is associated with impaired signal transduction within the RAAS
system, and or 3) said disease is facilitated or exacerbated by
activation of the AT1 receptor by angiotensin II, the initiating
step being the by binding of angiotensin II the AT1 receptor.
Because angiotensin II is a pro-inflammatory mediator, angiotensin
II-dependent diseases are expected to be inflammatory in nature
(Phillips M I, Kagiyama S. Curr Opin Investig Drugs 2002;
3:569-77). ARBs have the potential to ameliorate inflammatory
diseases, and because PPAR ligands also function as
anti-inflammatory agents with differing mechanisms of action, dual
ARB/PPAR ligands would have novel, more potent, synergistic effects
on inflammatory diseases (Tham D M, et al. Physiol Genomics 2002;
11:21-30).
[0055] An inflammatory disease is a disease associated dysfunction
of the immune system, exemplified as, but not limited to: 1)
increased production of inflammatory cytokines
(interleukin(IL)-1beta, IL-2, IL-6, IL-8, IL-112, tumor necrosis
factor-.alpha., interferon-.gamma., monocyte chemoattractant
protein-1), 2) increased conversion of Th2 lymphocytes to the Th1
phenotype or increased Th1/Th2 ratio, 3) inappropriate function of
NK (killer) T lymphocytes resulting in auto-antibodies and lack of
"self" recognition resulting in an autoimmune disease, 4) increased
expression or activation of inflammatory nuclear transcription
factors (NFAT, NF-.kappa.B, AP-1, JNK/STAT), 5) increased
expression of iNOS.
[0056] A proliferative disease is a disease associated with: 1)
pathological proliferation of normally quiescent cells, 2)
pathological migration of cells from their normal location (e.g.
metastasis of neoplastic cells), 3) pathological expression of
proteolytic enzymes such as the matrix metalloproteinases
(collagenases, gelatinases, elastases), 4) pathological
angiogenesis as in proliferative retinopathy and tumor
metastasis.
[0057] Angiogenesis is the process by which normally quiescent
endothelium responds to physiological or pathological stimuli (such
as proliferating endometrium, injury, tumor growth, or diabetic
retinopathy) resulting in pathological proliferation of blood
vessels (neovascularization). Pathological angiogenesis
(neovascularization) is an unregulated, unbridled process resulting
as in inappropriate vascular proliferation as in tumor
neovascularization, lymphangiogenesis, and tumor metastasis.
[0058] A degenerative disease is a disease associated with
deterioration or destruction normal tissue, resulting from immune
dysregulation resulting in the upregulation of one or more
inflammatory nuclear transcription factors, inflammatory cytokines
and other inflammatory molecules such as proteases (e.g. MMP-9) and
iNOS, leading to pathological degeneration of the respective cell
or tissue or organ which is the therapeutic target.
[0059] The term heart failure includes congestive heart failure,
heart failure with diastolic dysfunction, heart failure with
systolic dysfunction, heart failure associated with cardiac
hypertrophy, and heart failure that develops as a result of
chemically induced cardiomyopathy, congenital cardiomyopathy, and
cardiomyopathy associated with ischemic heart disease or myocardial
infarction.
[0060] The current invention relates to the surprising discovery
that certain ARBs can also function as PPARgamma activators and can
be used to prevent, delay, slow, arrest or treat insulin
resistance, pre-diabetes, glucose intolerance, impaired glucose
tolerance, the metabolic syndrome, type 2 diabetes, or other
insulin resistance syndromes, as well as other disorders responsive
to PPAR activators without increasing the risk for fluid retention,
peripheral edema, pulmonary edema, or congestive heart failure.
Thus, the current invention provides novel uses for certain ARBs
for the treatment or prevention of diseases known to be responsive
to drugs that increase PPARgamma activity including metabolic,
endocrine, proliferative, autoimmune, immunomodulatory and
inflammatory diseases and certain infective diseases. Accordingly,
the present invention includes the discovery of how to make,
identify, and use drugs that activate PPARgamma and that do not
increase the risk of fluid retention, edema, or congestive heart
failure like existing drugs that activate PPARgamma. This invention
describes the discovery that it is possible to make and use
compounds that have the dual ability to block or inhibit the
renin-angiotensin-aldosierone system and the ability to activate
PPARgamma. The invention provides specific examples of such
compounds not previously recognized to have this dual ability and
shows that these compounds can be used to treat conditions not
previously known to be responsive to such compounds. Thus, this
invention includes the surprising discovery that one can use
certain to treat disorders responsive to treatment with PPAR
activators.
[0061] The present invention provides novel uses for ARBs that also
activate PPARs for the treatment or prevention of diseases known to
be responsive to PPAR ligands, in particular PPARgamma partial
agonists or PPARgamma full agonists. Target diseases include
metabolic, endocrine, proliferative, degenerative, autoimmune,
atopic, and inflammatory diseases. The present invention also
relates to the identification of novel or previously unknown ARBs
that also activate PPARgamma and have a reduced propensity for
causing fluid retention, edema, or congestive heart failure
compared to other activators of PPARgamma. Thus, the present
invention includes the discovery of how to identify compounds that
block the rennin-angiotensin system and, at the same time, activate
PPARgamma but have a significantly lower risk of causing fluid
retention, edema, or congestive heart failure. The invention
provides specific examples of ARBs not previously recognized to
have this dual ability and reveals why these compounds can be used
to treat conditions not previously known to be responsive to said
compounds. Thus, this invention includes the surprising discovery
that one can use certain ARBs for the purpose of treating or
preventing disorders responsive to treatment with PPAR ligands,
said ligands having improved safety and therapeutic efficacy.
[0062] This invention relates to the unpredictable and surprising
discovery that certain compounds can block the rennin-angiotensin
system by antagonizing the AT1 receptor while activating PPARs, in
particular, PPARgamma.
[0063] In another aspect this invention relates to novel clinical
uses of ARBs in the prevention and treatment of PPAR-responsive
conditions or diseases.
[0064] In another aspect this invention relates to novel clinical
uses of ARBs in the prevention and treatment of PPAR-related
conditions or diseases mediated through PPAR-dependent regulation
of or interaction with related nuclear receptors, including the
retinoid X receptor (RXR), retinoid orphan-related receptor (ROR),
liver X receptor (LXR), farnesoid X receptor (FXR), vitamin D
receptor (VDR), estrogen receptors (ER-alpha and ER-beta),
glucocorticoid receptor (GR), thyroid receptor (TR) and androgen
receptor (AR).
[0065] In another aspect this invention relates to design and
identification of those ARBs that modulate the activity of PPARs,
thus providing for safer and enhanced therapeutic efficacy for
preventing or treating PPAR-mediated conditions or diseases, or the
end-organ complications of these diseases.
[0066] In another aspect, this invention relates to the
identification of low toxicity PPAR ligands that are effective ARBs
or ACE inhibitors by screening with AT1 receptor binding
assays.
[0067] In another aspect, this invention relates to methods for
identifying ARBs or derivatives thereof, that can be made to
further enhance their ability to activate PPAR and to more
effectively treat PPAR-responsive or PPAR-mediated diseases,
disorders or conditions.
[0068] Compounds according to the present invention have
renoprotective effects and are more effective for treating renal
diseases or limiting the rate of progression of renal diseases
(e.g. glomerular nephritis, glomerulosclerosis, nephrotic syndrome,
hypertensive nephrosclerosis, polycystic kidney diseases, and
diabetic nephropathy) compared to compounds that do not have this
dual ability to inhibit the activity of the renin angiotensin
aldosterone system and to activate PPARs.
[0069] This invention identifies ARBs that can be used as
monotherapy, or in combination with one or more other
pharmacological agents, or as adjunctive therapy to prevent, delay,
slow, arrest or treat:
[0070] 1. Metabolic diseases associated with insulin resistance
such as impaired glucose tolerance, glucose intolerance,
pre-diabetes, the metabolic syndrome (also termed metabolic
syndrome X or the dysmetabolic syndrome), obesity, type 2 diabetes
mellitus, gestational diabetes, polycystic ovarian syndrome,
Werner's syndrome;
[0071] 2. Dyslipidemias associated with hyperlipemia, elevated free
fatty acids, hypercholesterolemia, hypertriglyceridemia, elevated
low density lipoprotein-(LDL)-cholesterol, elevated very low
density lipoprotein-(VLDL)-cholesterol, elevated intermediate
density lipoprotein-(IDL)-cholesterol, or reduced high density
lipoprotein-(HDL)-cholesterol;
[0072] 3. Inflammatory skin diseases such as psoriasis, atopic
dermatitis, seborrheic dermatitis, solar dermatitis;
[0073] 4. Inflammatory or proliferative diseases such as
atherosclerosis, atherogenesis, vascular stenosis or restenosis,
rheumatoid arthritis, ulcerative colitis, Crohn's disease,
endometriosis; Inflammatory, neurodegenerative or neuropsychiatric
diseases such as Alzheimer's disease, Parkinson's disease, multiple
sclerosis, depression, psychoses; Benign, malignant tumor or
metastatic tumor growth;
[0074] 5. Neovascularization and pathological angiogenesis
associated with neoplasia, tumor growth and metastasis;
[0075] 6. Inflammatory or proliferative ocular diseases including
corneal angiogenesis, chorio-retinal retinopathy, age-related
macular degeneration and neovascularization, uveitis, glaucoma,
iritis, keratitis, retinitis;
[0076] 7. Pro-thrombotic diseases as in hypercoagulable or
thrombotic states, such as diseases associated with elevated
plasminogen activator inhibitor-1 (PAI-1), thombotic or
thromboembolic diseases, atheroma formation;
[0077] 8. Autoimmune diseases such as type 1 diabetes mellitus,
multiple sclerosis, Parkinson's disease, amyotropic lateral
sclerosis;
[0078] 9. Allograft rejection upon or subsequent to
transplantation, and complications associated with both acute and
chronic allograft rejection;
[0079] 10. Infective diseases caused by DNA viruses, RNA viruses
and retroviruses, including AIDS, SARS and hepatitis C;
[0080] 11. Infective diseases caused by prions, such as kuru,
Cretzfeld-Jackob disease and spongiform encephalopathies;
[0081] 12. Complications associated with viral and prion-related
infections, including CNS-related complications and CNS-related
degenerative conditions that result in encephalopathy, dementia and
cachexia;
[0082] 13. Cachexia associated with chronic diseases such as CHF,
cancer, multiple sclerosis, chronic infections, anorexia nervosa,
bullemia;
[0083] 14. CD-36 mediated diseases such as certain metabolic
diseases, retinitis pigmentosa and malaria
[0084] 15. Conditions such as obesity, including methods for
controlling appetite or food intake, diet and anorexia.
[0085] A compound or a pharmaceutical composition according to the
present invention is a PPARgamma activator which has less toxicity
than other PPAR activators of the current art. Less toxicity
principally refers to substantially reduced potential for fluid
retention, edema or heart failure. Said compound or pharmaceutical
composition according to the present invention may also be used
prevent, delay, slow, arrest or treat chronic medical pathologies
and diseases, including: a) diabetic complications and
diabetes-associated conditions including steatohepatitis,
neuropathy, nephropathy, retinopathy, chorioretinopathy, choroidal
neovascularization, retinal neovcascularization, macular
degeneration, retinal detachment, glaucoma, cataract,
microangiopathy, atherosclerosis, ischemic heart disease, ischemic
cerebrovascular disease, stroke, peripheral arteriosclerosis,
cerebral arteriosclerosis, coronary arteriosclerosis,
hyperinsulinemia-induced sensory disorder, obesity, heart failure,
myocardial infarction, angina pectoris, cerebral infarction,
chronic cardiomyopathy, cardiac fibrosis, renal disorders,
glomerular nephritis, glomerulosclerosis, nephrotic syndrome,
hypertensive nephrosclerosis, terminal renal disorders,
microangiopathy, atherosclerosis, ischemic heart disease, ischemic
cerebrovascular disease, diabetic cachexia, and the like; b)
cachexia resulting from chronic diseases or conditions including
carcinomatous cachexia, hemophathic cachexia, endocrinopathic
cachexia, infectious cachexia, cachexia induced by acquired
immunodeficiency syndrome, cachexia associated with congestive
heart failure or chronic cardiomyopathy, anorexia nervosa, and the
like; c) degenerative diseases including osteopenia, osteoporosis,
muscular dystrophy, rheumatoid arthritis, spondylitis deformans,
osteoarthritis, lumbago, gout, neuralgia, gastritis, hepatitis,
pneumonia, pancreatitis and the like. In addition, a compound
according to the invention may also be employed as a pharmaceutical
for controlling appetite or food intake, diet and anorexia.
[0086] A compound or a pharmaceutical composition according to the
present invention has a blood sugar reducing effect, a blood lipid
reducing effect, a blood insulin reducing effect, an insulin
sensitivity enhancing effect, an insulin resistance improving
effect, a body weight reducing effect, a central body girth
(measured as waist:hip ratio) reducing effect, a body fat mass
reducing effect, through effects on PPARgamma activity,
PPARgamma-RXR, or through effects on relater nuclear receptors,
including FXR, LXR, ROR, cAMP-response element-binding protein
(CREB), CREB-binding protein (CBP), CBP/p300, sterol regulatory
binding proteins (SREBPs), steroid receptor coactivator-1 (SRC-1),
PPARgamma coactivator-1 alpha (PGC-1alpha), PPARgamma
coactivator-1beta (PGC-1beta) and PPAR-binding protein (PBP).
[0087] While the dose of a compound or a pharmaceutical composition
according to the present invention varies depending on various
factors such as the subject to be treated, the administration
route, the disease or the condition to be treated, a compound
according to the present invention as an active ingredient may for
example be given orally to an human at a daily dose of about 0.05
to 100 mg/kg body weight, preferably about 0.1 to 10 mg/kg body
weight, preferably one to three times a day, with a single dose
providing therapeutic efficacy for at least 24 hr being preferred.
It is also contemplated that the therapies described in the present
invention is applicable to children and adults.
[0088] A compound according to the present invention has a blood
sugar reducing effect, a blood lipid reducing effect, a blood
insulin reducing effect, an insulin sensitivity enhancing effect,
an insulin resistance improving effect, a body weight reducing
effect, a central body girth (measured as waist:hip ratio) reducing
effect, a body fat mass reducing effect, through ligand-dependent
PPAR activity or PPAR-related nuclear receptor function activities.
A PPAR is a nuclear transcription factor, and the term is used here
to encompass PPAR.gamma., PPAR.alpha., PPAR.delta. nuclear
receptors that function as DNA-binding transcription factors having
as a secondary modulating ligand for a dimeric nuclear receptor
partner, such as an oil-soluble vitamin (vitamin A, vitamin D), a
retinoid, or steroid hormone, and may be any of a monomer receptor,
a homodimer receptor and a heterodimer receptor. A monomer receptor
is exemplified by retinoid O receptor (hereinafter abbreviated
occasionally as ROR.alpha. (GenBank Accession No.L14611) ROR.beta.
(GenBank Accession No.L14160), ROR.gamma. (GenBank Accession
No.U16997); Rev-erb.alpha.. (GenBank Accession No.M24898),
Rev-erb.beta.. (GenBank Accession No.L31785); ERR.alpha.. (GenBank
Accession No.X51416), ERR.beta. (GenBank Accession No.X51417);
Ftz-FI.alpha.. (GenBank Accession No.S65876), Ftz-FI.beta..
(GenBank Accession No.M81385); TIx (GenBank Accession No.S77482);
GCNF (GenBank Accession No.U14666) and the like. A homodimer
receptor may for example be a homodimer formed from retinoid X
receptor (hereinafter abbreviated occasionally as RXR.alpha..
(GenBank Accession No.X52773), RXR.beta.. (GenBank Accession
No.M84820), RXR.gamma.. (GenBank Accession No.U38480); COUP.alpha.
(GenBank Accession No.X12795), COUP.beta. (GenBank Accession
No.M64497), COUP.gamma. (GenBank Accession No.X12794); TR2 (GenBank
Accession No.M29960), TR2.beta. (GenBank Accession No.L27586); or,
HNF4.alpha. (GenBank Accession No.X76930), HNF4..gamma.. (GenBank
Accession No.Z49826) and the like. A heterodimer receptor may for
example be a heterodimer formed from retinoid receptor X
(RXR.alpha., RXR.beta. or RXR.gamma.) described above together with
one receptor selected from the group consisting of retinoid A
receptor (hereinafter abbreviated occasionally as RAR.alpha.
(GenBank Accession No.X06614), RAR.beta. (GenBank Accession
No.Y00291), RAR.gamma. (GenBank Accession No.M24857); a thyroidal
hormone receptor (hereinafter abbreviated occasionally as TR.alpha.
(GenBank Accession No.M24748), TR13 (GenBank Accession No.M26747);
a vitamin D receptor (VDR) (GenBank Accession No.J03258); a
peroxisome proliferator-activated receptor (hereinafter abbreviated
occasionally as PPAR.alpha. (GenBank Accession No.L02932),
PPAR.beta. (PPARdelta) (GenBank Accession No.U10375), PPAR.gamma.
(GenBank Accession No.L40904); LXR.alpha. (GenBank Accession
No.U22662), LXR.beta. (GenBank Accession No.U14534); FXR (GenBank
Accession No.U18374); MB67 (GenBank Accession No.L29263); ONR
(GenBank Accession No.X75163; and NUR..alpha. (GenBank Accession
No.L13740), NUR..beta.. (GenBank Accession No.X75918), NUR..gamma..
(GenBank Accession No.U12767).
[0089] The current invention constitutes the surprising finding
that certain ARBs can activate PPAR.gamma., promote adipogenesis,
lower (improve) insulin resistance, and can be used to treat or
prevent the metabolic syndrome and components thereof (see
definitions) and type 2 diabetes. Among the ARBs presently approved
for human use telmisartan and irbesartan are specific examples of
compounds of this invention, and can surprisingly be used to treat
or prevent insulin resistance, the metabolic syndrome and type 2
diabetes (i.e. lower hyperinsulinemia and/or hyperglycemia), lower
triglycerides, and elevate HDL-cholesterol. An extension of this
invention is the predictive design of derivatives of existing ARBs
to improve their insulin resistance-lowering activity by increasing
the EC50 for activation of PPAR.gamma..
[0090] It has been previously shown that the risk for diabetes in
patients given ARBs is lower than that in patients given other
antihypertensive drugs. However, until the current discovery
described herein, it was not known that these drugs could activate
PPAR.gamma. and it could not have been predicted that these drugs
could be used to treat insulin resistance syndromes such as type 2
diabetes or other conditions known to be treatable by PPAR ligands.
For example, the lower risk of diabetes reported in patients given
ARBs versus .beta.-blockers (Dahlof B, et al. Lancet 2002;
359:995-1003) could have been due to the fact that .beta.-blockers
aggravate insulin resistance and therefore, the results of clinical
studies comparing ARBs to other agents cannot be used to predict
whether ARBs can be used to treat diabetes or other disorders
responsive to PPAR.gamma. ligands.
[0091] Because ARBs do not cause substantial fluid retention and do
not increase the risk for edema and heart failure, they represent a
significant improvement over the currently recognized PPAR ligands.
Specific examples of ARBs that activate PPAR.gamma. are provided
together with a description of novel clinical uses of these agents
and instructions for such use. This invention also describes the
novel finding that one can derive new ARBs with greater ability to
activate PPARs than existing ARBs and that such ARBs with enhanced
ability to activate PPARs can be used to prevent or treat clinical
disorders known to be responsive to PPAR ligands without causing
the degree or extent of side effects of fluid retention, edema, or
congestive heart failure caused by currently marketed PPAR ligands.
Surprisingly, one can also make modifications to currently
available ARBs that will significantly enhance their ability to
activate PPARs and therefore enhance their ability to treat
disorders known to be responsive to PPAR ligands. Such compounds
also represent an improvement over existing ARBs as they have
greater ability to activate PPARs and therefore have the added
benefits of improving clinical disorders that are responsive to
treatment with PPAR activators. Using the methods of this
invention, one can identify, develop, and use PPAR ligands that
have the ability to inhibit ACE activity or block angiotensin
receptors. Such compounds represent a novel approach to treating
disorders known to be responsive to PPAR ligands because they do
not promote fluid retention, edema, or congestive heart failure to
the extent that currently available PPAR ligands are know to
do.
[0092] Specific examples of ARBs that activate PPAR.gamma. are
provided together with a description of novel clinical uses of
these agents and instructions for such use. This invention also
describes the novel finding that one can derive new ARBs with
greater ability to activate PPARs than existing ARBs and that such
ARBs, having enhanced ability to activate PPARs, can be used to
prevent or treat clinical disorders known to be responsive to PPAR
ligands without causing the degree or extent of side effects of
fluid retention, edema, or congestive heart failure as do currently
marketed PPAR.gamma. ligands. Surprisingly, one can structurally
modify currently available ARBs to significantly enhance their
ability to activate PPARs and therefore enhance their ability to
treat disorders known to be responsive to PPAR ligands. Such
compounds also represent an improvement over existing ARBs in that
they more effectively activate PPARs and therefore have the added
benefits of improving clinical disorders that are responsive to
treatment with PPAR activators. Using the methods of this
invention, one can identify, develop, and use PPAR ligands that
have the ability to antagonize the AT1 receptor. Such compounds
represent a novel approach to treating disorders known to be
responsive to PPAR ligands because they do not promote fluid
retention, edema, or congestive heart failure to the extent that
currently available PPAR ligands are know to do. While not wishing
to be bound by theory, PPAR.gamma. ligands cause fluid retention
through a number of mechanisms. A surprising feature of this
invention is that the fluid retention usually caused by PPAR.gamma.
ligands can be prevented or attenuated by blockade of AT1
receptors. Because blockade of the AT1 receptor does not always
attenuate or prevent fluid retention in some animal models treated
with PPAR.gamma. ligands, and because multiple mechanisms may be
involved in the fluid retention caused by PPAR.gamma. ligands, it
could not have been predicted that blockade of AT1 receptors could
prevent or attenuate the fluid retention caused by PPAR.gamma.
ligands in humans. Also surprisingly, by administering an ARB prior
to or concurrently with compounds that activate PPARgamma either as
separate pills or tablets, or by administering both drugs
formulated in a single pill or tablet, one can also treat glucose
intolerance or type 2 diabetes and other PPAR responsive disorders
without causing fluid retention, edema, or congestive heart
failure.
[0093] Because PPAR.gamma. is not recognized to be structurally
related to the AT1 receptor, ARBs would not be expected to activate
PPAR.gamma.. Thus, it could not have been predicted that one could
use any existing ARB to activate PPAR.gamma.. Therefore, one could
not have predicted that ARBs would be useful to treat disorders
responsive to PPAR.gamma. ligands or that one could design drugs
that have the ability to block the AT1 receptor while also having
the ability to activate PPAR.gamma.. This invention describes the
surprising discovery that compounds can be designed to antagonize
the AT1 receptor while also possessing the ability to activate
PPAR.gamma., and that such compounds can be surprisingly useful for
treating conditions known to be responsive to PPAR.gamma. ligands
without promoting fluid retention, edema, or heart failure. Also
surprisingly, by administering an ARB that also activates
PPAR.gamma., one can also treat insulin resistance, the metabolic
syndrome, glucose intolerance, type 2 diabetes, polycystic ovarian
syndrome, as well as other PPAR.gamma.-responsive disorders without
causing fluid retention, edema, or congestive heart failure. These
findings suggested that like the anti-diabetic thiazolidinedione
PPAR.gamma. agonists, telmisartan may also improve insulin
resistance. We determined that administration of telmisartan to a
patient with the metabolic syndrome improved insulin resistance as
determined by reduction of the HOMA-IR score (see definitions).
When administered to a patient with type 2 diabetes, telmisartan
lowered the hyperglycemia, lowers plasma triglycerides, and
elevated blood HDL-cholesterol. These finding led to the surprising
discovery, and invention, that ARBs that also activate PPAR.gamma.
are useful for preventing and treating the metabolic syndrome, type
2 diabetes, and improving lipid metabolism by lowering
triglycerides and elevating HDL-cholesterol. These
insulin-sensitizing, antidiabetic effects are limited to certain
ARBs, such as telmisartan and irbesartan. ARBs such as valsartan
and eprosartan which do not activate PPAR.gamma. at doses
reasonably achievable at therapeutic doses, did not promote
adipogenesis, a property of telmisartan and the insulin-sensitizing
thiazolidinedione PPAR.gamma. agonists. Thus, the property of
reducing insulin resistance is restricted within the class of
non-peptide ARBs known as "sartans", and are unpredictable
surprising and non-obvious. This invention discloses methods of
determining which "sartans" or other AT1 receptor antagonists may
function as an insulin-sensitizing, insulin resistance-improving or
anti-diabetic agent.
[0094] Insulin resistant states predispose to inflammatory,
proliferative and degenerative diseases such as atherosclerosis,
atherogenesis, vascular stenosis or restenosis after invasive
intravascular procedures, cardiomyopathy, and myocardial fibrosis.
Moreover, the excessive use of glucocorticoids and/or
immunosuppressive agents, as in the treatment of chronic
inflammatory diseases and complications of immunosuppression in
allograft rejection, such as osteoporosis, Cushing's disease,
lipodystrophy, insulin resistance, type 2 diabetes, hyperlipidemia,
transplantation-related hypertension, atherosclerosis, renal
disease, arteritis and endarteritis. This invention predicts that
administration of an ARB that also activates PPAR.gamma. would
result in the clinical improvement of these conditions.
Uses of the Invention
[0095] The methods of treatment provided by this invention are
practiced by administering to a human or vertebrate animal in need
a dose of a compound, or a pharmaceutically acceptable salt, ester,
solvate or tautomer thereof, that blocks or antagonizes the
angiotensin II type 1 receptor and activates either PPARgamma alone
or in combination with PPARalpha, or PPARdelta both PPARalpha and
PPAR gamma. In another aspect, the novel compounds used to practice
this invention are set forth above. The specific diseases and
associated disorders that can be treated with the compounds
described in this invention are listed in Tables I through X.
TABLE-US-00001 TABLE I Examples of dermatological disorders and
inflammatory skin disorders treatable using compounds of this
invention Kertinizing skin diseases, keratitis, hidradenitis,
ichthyosis, melasma Psoriasis (all forms, including p. vulgaris, p.
guttata, p. discoidea, p. anthropica, p. universalis) Acne (all
forms, including a. vulgaris, a. rosacea, a. inversa, cystic acne)
Warts, verruca (all forms, including common warts, anogenital
(venereal) warts, viral warts including human papilloma virus (HPV)
infections, conjunctival warts, oral/buccal warts) Acute and
chronic dermatitides (inflammation of the skin), atopic dermatitis,
allergic dermatitis, contact dermatitis, cosmetic dermatitis,
chemical dermatitis, seborrheic dermatitis, solar dermatitis, acute
and chronic eczema, diaper rash, sunburn Lupus associated skin
lesions Keratoses such as seborrheic keratosis, senile keratosis,
actinic keratosis, photo-induced keratosis, skin aging, thinning
skin, dry skin, wrinkle formation, photo-induced skin aging,
keratosis follicularis Keloids and prophylaxis against keloid
formation Leukoplakia, lichen planus Urticaria, pruritus Androgenic
alopecia in men and women, hirsutism in women
[0096] TABLE-US-00002 TABLE II Examples of psychiatric disorders
treatable using compounds described in this invention Depression,
primary depression or depression secondary to chronic diseases and
medications Dysphoric mood disorders Obsessive compulsive disorder
Dysthymic disorders Manic depressive (unipolar or bipolar) disorder
Anxiety states including panic disorder and agoraphobia Post
menstrual syndrome Schizophrenia Chronic fatigue syndrome Substance
abuse and drug addiction Anorexia nervosa and anorexia bullemia
[0097] TABLE-US-00003 TABLE III Examples of
neurological/neurodegenerative disorders and CNS inflammatory
disorders treatable using compounds described in this invention
Migraine headaches (e.g. vascular headaches, common migraine)
Primary (e.g. Alzheimer's disease) and secondary (e.g. HIV-related)
dementias Degenerative CNS diseases (e.g. Parkinson's disease,
amyotropic lateral sclerosis) Demyelinating diseases (e.g.multiple
sclerosis, Guillain-Barre syndrome) Pain disorders including
algesia, hyperalgesia, acute and chronic pain, allodynia Primary
and secondary encephalitis and encephalomyelitis (e.g. autoimmune
encephalomyelitis, allergic encephalomyelitis) Primary and
secondary neuritis, autoimmune neuritis Other autoimmune diseases
(e.g. myesthenia gravis, Eaton-Lambert syndrome) Congenital and
secondary ataxias
[0098] TABLE-US-00004 TABLE IV Examples of inflammatory and
metabolic disorders associated with allograft transplanatation
treatable using compounds described in this invention The compounds
described herein are useful as monotherapy or adjunctive therapy
with existing immunosuppressive agents for the promotion and
maintenance of allograft survival, post-transplantation. Examples
of inflammatory and proliferative conditions or diseases associated
with allograft transplantation and immune suppression include: 1.
Acute allograft rejection 2. Chronic allograft rejection 3. Graft
versus host disease 4. Post-transplantation de novo malignancy
(e.g. lymphoma and epidermal cancers) 5. Osteoporosis and
osteopenia 6. Hyperlipidemia 7. Insulin resistance and diabetes
mellitus 8. Hypertension 9. Atherosclerosis 10. Endarteritis
associated with heart allograft transplantation 11.
Glomerulonephritis associated with renal allograft transplantation
12. Cardiomyopathy and congestive heart failure associated with
allograft transplantation, in particular heart transplantation
[0099] TABLE-US-00005 TABLE V Examples of diseases of various organ
systems treatable using compounds described in this invention Organ
System Disease/Pathology Cardiovascular Metabolic disorders
including hypertension, vasculo-occlusive diseases including
atherosclerosis, arteritis, endarteritis, endocarditis,
myocarditis, arterial plaque (fibrous cap) rupture, thrombosis,
restenosis after any invasive vascular procedures; acute coronary
syndromes such as unstable angina, myocardial infarction,
myocardial ischemia and other ischemic cardiomyopathies, non-
ischemic cardiomyopathies, post-myocardial infarction
cardiomyopathy and myocardial fibrosis, drug-induced
cardiomyopathy. Endocrine Metabolic disorders including obesity,
type 1 diabetes mellitus, type 2 diabetes mellitus, gestational
diabetes; impaired glucose tolerance, Cushing's syndrome (e.g.
secondary to chronic glucocorticoid therapy), polycystic ovarian
syndrome, osteoporosis, osteopenia, accelerated aging of tissues
and organs, e.g. Werner's syndrome. Urogenital Prostatitis,
endometritis, endometriosis, benign prostatic hypertrophy,
leiomyoma, polycystic kidney disease (e.g. autosomal dominant PKD),
acute tubular necrosis, nephrotic syndrome, diabetic nephropathy,
glomerulonephritis, erectile dysfunction in men and women Pulmonary
Asthma, chronic obstructive pulmonary disease (COPD), reactive
airway disease, pulmonary fibrosis, pulmonary hypertension.
Connective Rheumatoid arthritis, Raynaud's phenomenon/disease,
Sjogren's tissue syndrome, systemic sclerosis, systemic lupus
erythematosus, Joint inflammatory bowel disease (ulcerative
colitis, Crohn's disease) vasculitides, ankylosing spondylitis,
osteoarthritis, reactive arthritis, psoriatic arthritis,
fibromyalgia, osteoarthritis, sarcoidosis. Liver/Other Hepatic
fibrosis, hepatic cirrhosis, hepatic steatosis, all etiologies,
e.g. alcohol-induced (e.g. ethanol), drug-induced (e.g. tylenol),
and toxin-induced (e.g. mushroom poisoning) Fibrocystic breast
disease, fibroadenoma, endometriosis
[0100] TABLE-US-00006 TABLE VIa Examples of neoplastic diseases
treatable using compounds described in this invention Organ System
Malignancy/Cancer type Skin Basal cell carcinoma, melanoma,
squamous cell carcinoma; cutaneous T cell lymphoma; Kaposi's
sarcoma. Hematological Acute leukemia, chronic leukemia and
myelodysplastic syndromes. Urogenital Prostatic, renal and bladder
carcinomas, anogenital carcinomas including cervical, ovarian,
uterine, vulvar, vaginal, and those associated with human papilloma
virus infection. Neurological Gliomas including glioblastomas,
astrocytoma, ependymoma, medulloblastoma, oligodendroma;
meningioma, pituitary adenoma, neuroblastoma, craniopharyngioma.
Gastrointestinal Colon, colorectal, gastric, esophageal,
mucocutaneous carcinomas. Breast Breast cancer including estrogen
receptor and progesterone receptor positive or negative subtypes,
soft tissue tumors. Metastasis Metastases resulting from all
neoplasms. Other Angiomata, angiogenesis associated with the
neoplasms.
[0101] TABLE-US-00007 TABLE VIb Examples of neoplastic diseases
treatable using compounds described in this invention (cont'd)
Location Malignancy/Cancer type Various fibrosarcoma, myxosarcoma,
liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,
angiosarcoma, enthotheliosarcoma, lymphangiosarcoma,
lymphangioendotheliosarcoma, synovioma, mesothelimoa, Ewing's
tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, basal
cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous
gland carcinoma, papillary carcinoma, papillary adenocarcinomas,
cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma,
renal cell carcinoma, hepatoma, bile duct carcinoma,
choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,
cervical cancer, testicular tumor, lung carcinoma, small cell lung
carcinoma, bladder carcinoma, epithelial carcinoma, glioma,
astrocytoma, medulloblastoma, craniopharyngioma, ependymoma,
pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma,
meningioma, melanoma, neuroblastoma, and retinoblastoma.
[0102] TABLE-US-00008 TABLE VII Examples of viral infections and
related pathologies treatable according to the methods of this
invention Virus Viral infection/cancer or other virus-associated
pathology HTLV T-cell leukemia/lymphoma, HTLV-associated
arthritides/myelopathies. HPV Cervical and anogenital cancers;
common and anogenital (venereal) warts, including verrucae,
condyloma or condyloma acuminata, related non-neoplastic (e.g.,
keratitis, conjunctivitis) pre-neoplastic and neoplastic (e.g.,
conjunctival epithelial neoplasms) diseases of the eye. HAV, HBV,
HCV Hepatitis, hepatocellular carcinoma, lymphoma. CMV Hepatitis,
retinitis, meningitis. HSV, VSV Related mucocutaneous,
oropharyngeal and genital diseases, related skin and respiratory
infections, varicella-zoster, chicken pox, herpes zoster,
post-herpetic neuralgia, conjunctivitis, keratoconjunctivitis,
keratitis. HHV Exanthem subitum, infectious mononucleosis. EBV
Infectious mononucleosis, chronic fatigue syndrome, lymphoma,
conjunctivitis, keratitis, and related infections of the eye.
Adenoviruses Upper and lower respiratory tract infections,
pneumonia, conjunctivitis. RSV Upper and lower respiratory tract
infections, pneumonia. PMV Mumps and related manifestations, e.g.,
conjunctivitis. MV, RV Measles, Rubella ("German measles") and
related manifestations. Coxsackie viruses Conjunctivitis, diabetes
mellitus, respiratory infections. Influenza viruses Upper and lower
respiratory tract infections, pneumonia. HIV, Human
Immunodeficiency Virus; HTLV, Human T-cell Lymphocyte Virus; HPV,
Human Papilloma Virus; HAV, Hepatitis A Virus; HBV, Hepatitis B
Virus; HAV, Hepatitis C Virus; CMV, Cytomegalovirus; HSV, Herpes
Simplex Virus (Types I & II); HHV, Human Herpes Virus; EBV,
Epstein-Barr Virus; RSV, Respiratory Syncytial Virus; VZV,
Varicella-Zoster Virus; PMV, Paramyxovirus; MV, Measles (Rubeola)
Virus; RV, Rubella Virus
[0103] TABLE-US-00009 TABLE VIII HIV related infections and
diseases treatable using compounds described in this invention
Organ system Viral infection/manifestation or other HIV-associated
disease Immunologic AIDS, primary HIV infection. Dermatological
Anogenital cancers including rectal and cervical cancer, Kaposi's
sarcoma, atopic dermatitis, squamous cell carcinoma, hairy
leukoplakia, molluscum contagiosum, warts (HPV infections),
seborrheic dermatitis, psoriasis, xeroderma, HSV and varicella-
zoster infections. Hematologic Non-Hodgkin's lymphoma, B cell
lymphoma, anemia, neutropenia, thrombocytopenia. Gastrointestinal
Anorexia, gastroparesis, diarrhea, malabsorption, gastrointestinal
CMV infections, esophagitis, colitis, hepatitis, lymphoma.
Ophthalmic Conjunctivitis, keratitis, keratoconjunctivitis,
uveitis, retinitis, chorioretinitis, CMV retinitis, iridocyclitis,
vitreitis, choroiditis, papilledema, Kaposi's sarcoma, lymphoma,
ocular palsies, conjunctival warts, pre-neoplastic and neoplastic
diseases of the eye. Cardiac Myocarditis, endocarditis,
pericarditis. Pulmonary CMV pneumonitis, lymphoid interstitial
pneumonitis. Nephrologic HIV nephropathy, renal cell carcinoma,
amyloidosis, uropathy. Rheumatologic Arthralgia, fibromyalgia,
Reiter's syndrome, psoriatic arthritis, vasculitis. Neurologic
Dementia, viral meningitis, viral encephalitis, HIV encephalopathy,
progressive multifocal leukoencephalopathy, CNS lymphoma,
peripheral and autonomic neuropathies. Psychiatric Dysphoric mood
disorders, depression, depression associated with chronic diseases
and medications, bipolar disorder, anxiety disorders, chronic
fatigue syndrome, chronic pain, psychoses, substance abuse
disorders and drug addiction. General Lymphoma, metastatic
lymphoma, Kaposi's sarcoma, wasting syndrome, psychosis.
[0104] TABLE-US-00010 TABLE IXa Diseases of the eye treatable using
compounds described in this invention Disease Virus 1. Inflammatory
eye diseases associated with viral infections Blepharitis HSV, VZV,
Vaccinia, HPV, molluscum contagiosum Conjunctivitis HSV, VZV, EBV,
Adenovirus, Vaccinia, Variola, HPV, molluscum contagiosum,
influenza Follicular c. Newcastle, measles, mumps, rubella,
molluscum contagiosum Hemorrhagic c. Enterovirus, coxsackie
Catarrhal c Rubella Keratitis HSV, VZV, EBV, Adenovirus, Vaccinia,
Variola, HPV, molluscum contagiosum Keratoconjunctivitis HSV, VZV,
EBV, Adenovirus, Vaccinia, Variola, HPV, molluscum contagiosum
Retinitis CMV Uveitis HPV Conjunctival warts HPV Epithelial
neoplasms HPV 2. Oularplastic diseases Benign tumors
Keratocanthoma, molluscum contagiosum, dermoid cysts, neurofibroma,
neurofibromatosis, schwannoma (neurilemoma), pleiomorphic adenoma
Malignant tumors Basal cell carcinoma, squamous cell carcinoma,
mucoepidermoid carcinoma, melanoma, retinoblastoma, embryonal
rhabdomyosarcoma, meningioma, adenoid cystic carcinoma, lymphoid
tumors of the orbit, mesenchymal tumors (fibrous hystiocytoma) of
the orbit, nasopharyngeal carcinoma. Vascular lesions Hemangioma,
lymphangioma
[0105] TABLE-US-00011 TABLE XIb Ophthalmic diseases treatable using
compounds described in this invention (cont'd) Disease
Category/Examples of Diseases, Causes or Associated Conditions*
Conjunctivitis Acute allergic conjunctivitis (e.g. drug-related
inflammation, hypersensitivity reactions), chronic (vernal)
conjunctivitis, contact lens-associated conjunctivitis, e.g. giant
papillary conjunctivitis, conjunctival ulceration, including
ulceration associated with mucous membrane, conjunctival warts
Blepharitis Inflammatory etiologies, e.g. blepharitis secondary to
rosacea Ophthalmic fibrosis Steven's-Johnson syndrome with
progressive fibrosis and scarring, cicatrization and symblepharon.
Corneal injury Corneal abrasion or ulceration (e.g. contact
lens-related injury), or corneal injury of any etiology*. Dry eye
syndrome See Table below Pterygium, pinguecula Pemphigoid Includes
ophthalmic pemhigori Scleritis/Episcleritis Iridocyclitis
Endophthalmitis Uveal tract diseases Including glaucoma (primary
and secondary etiologies) Uveitis, uveoretinitis, panuveitis, all
etiologies* Vitreitis, retinitis e.g. congenital retinitis,
retinitis pigmentosa Infectious retinitis Viral (e.g. herpes,
cytomegalovirus, HIV), tuberculous, syphititic, fungal (e.g.
histoplasmosis) Chorioretinopathies Chorioretinitis, choroiditis,
vitreitis, Retinopathies e.g. Diabetic retinopathy, hypertensive
retinopathy Maculopathies age-related-macular degeneration, white
dot syndromes Cataract Related to diabetes, age, collagen vascular
diseases Ocular palsies *Etiologies of ophthalmic diseases
treatable according to the methods of this invention include
diseases induced or caused by physical agents (e.g. UV radiation),
chemical agents (e.g. acids, caustic solvents) immunological
etiologies (e.g. collagen vascular diseases, auto-immune, T
lymphocyte-related), infectious agents such as viruses (HSV, CMV,
HIV), mycoplasma, tuberculosis, syphilis, fungae
(histoplasmosis)
[0106] TABLE-US-00012 TABLE IXc Ophthalmic diseases treatable using
compounds described in this invention (cont'd) - Etiologies of dry
eye syndrome I. Conditions Characterized by Hypofunction of the
Lacrimal Gland: A. Congenital Familial dysautonomia (Riley-Day
syndrome), aplasia of the lacrimal gland (congenital alacrima),
trigeminal nerve aplasia, ectodermal dysplasia B. Acquired 1.
Systemic Diseases, e.g. Sjogren's Syndrome, progressive systemic
sclerosis, sarcoidosis, leukemia, lymphyoma, amyloidosis,
hemochromatosis, 2. Infection, e.g. mumps 3. Injury, e.g. surgical
removal of lacrimal gland, irradiation, chemical burn 4.
Medications, e.g. antihistamines, antimuscarinics (atropine,
scopolamine), general anesthetics (halothane, nitrous oxide),
.E-backward.- adrenergic blockers (timolol, practolol), neurogenic,
neuroparalytic (facial nerve palsy) II. Conditions Characterized by
Mucin Deficiency Avitaminosis A, Stevens-Johnson syndrome, ocular
pemphigoid, chronic conjuncitivitis (e.g. trachoma), chemical
burns, drugs and medications III. Conditions Characterized by Lipid
Deficiency Lid margin scarring, blepharitis IV. Defective Spreading
of Team Film Caused by the Following: A. Eyelid abnormalities 1.
Defects, colboma 2. Ectropion or entropion 3. Keratinization of lid
margin 4. Decreased or absent blinking secondary to: neurologic
disorders, hyperthyroidism, contact lens, drugs and medications,
herpes simplex keratitis, leprosy, conjunctival abnormalities,
pterygium, symblepharon, proptosis
[0107] TABLE-US-00013 TABLE IXd Ophthalmic diseases treatable using
compounds described in this invention (cont'd) - Non-hereditary and
hereditary degenerative diseases Macular disorders: All etiologies
and manifestations, including age-related macular degeneration,
exudative macular degeneration, atrophic macular degeneration,
crystalline retinopathies, retinal toxicosis of systemic
medications, idiopathic central serous choroidiopathy, macular
edema Retinovascular diseases and Retinopathy, vasculo-occlusive
r., ischemic retinopathies: r., idiopathic r., hypertensive r.,
proliferative r., diabetic r., vitreoretinopathy, vasculopathies
associated with telangiectasias or aneurysms, retinopathies
associated with lupus erythematosus, rheumatoid arthritis, multiple
sclerosis, myasthenia gravis, uveoretinitis or diabetes mellitus,
glaucomatous retinopathies Glaucoma: All etiologies and
manifestations, including primary and secondary open- angle
glaucoma, angle-closure glaucoma, glaucoma associated with
intraocular inflammation, elevated intraocular pressure associated
with acute glaucoma, steroid-induced glaucoma, glaucoma associated
with intraocular hemorrhage, pseudoexfoliative syndrome,
glaucomatous optic neuropathy and other degenerative changes (e.g.
retinopathy) associated with glaucoma Cataract: All etiologies and
manifestations, including age-related (UV radiation) cataract,
cataract associated with systemic diseases such as collagen
vascular disease, diabetes mellitus, Wilson's disease Other
diseases: Primary or secondary retinal detachment
[0108] TABLE-US-00014 TABLE IXe Ophthalmic diseases treatable using
compounds described in this invention (cont'd) - Congenital
degenerative retinopathies I. Primary pigmented retinopathies, all
gene types Autosomal dominant retinitis pigmentosa, e.g. rod-cone
and cone-rod degenerations Autosomal recessive retinitis
pigmentosa, e.g. rod-cone and cone-rod degenerations, Lerner's
amaurosis congenita X-linked recessive pigmented retinopathies,
e.g. choroideremia 2. Secondary pigmented retinopathies
(retinopathies associated with systemic diseases) Autosomal
dominant pigmented retinopathies, e.g. Paget's disease,
Charcot-Marie-Tooth, disease, Steinert's disease, Pierre-Marie
syndrome Autosomal recessive pigmented retinopathies, e.g. diabetes
mellitus, mannosidoses, mucopolysccharidoses, Batten's d., Refsum's
d., Usher syndrome X-linked recessive pigmented retinopathies, e.g.
Hunter syndrome
[0109] TABLE-US-00015 TABLE X Diseases or conditions treatable
using compounds described in this invention I. Promote healing in
the following clinical situations: Surgical or traumatic wounds to
healthy tissues or organs Wounds caused by chemical or physical
agents, e.g. ulcers caused by caustic or erosive chemicals,
pressure sores, etc. Wounds associated with disease states, e.g.
diabetic ulcers etc. Wounds in diseased tissues or organs II.
Promote cell survival and prevent apoptosis in neurodegenerative
diseases: Alzheimer's disease Parkinson's disease Amyotrophic
lateral sclerosis Spinal cord ischemia, injury or transection
secondary to trauma or disease III. Attenuation or arrest of the
following conditions or processes. The natural aging of cells and
tissues Aging induced by chemical or physical agents, e.g.
sun-induced skin aging Accelerated aging associated with diseases,
e.g. Werner's syndrome IV. Vitalization and revitalization of
organs and tissues Promoting cell growth and preventing cell death
in the aging process Promoting therapeutic or non-pathological
angiogenesis as a therapeutic approach to treating diseases such as
congestive heart failure and cardiomyopathy Promoting growth of
organs and tissues for repair or transplantation
[0110] The oral route of administration is the preferred mode for
treatment or prevention of type 2 diabetes, the metabolic syndrome,
and most other chronic disorders. Therapeutic agents of the
invention are usually delivered or administered topically for
treating disorders involving the eye or the skin except in some
cases where oral administration is the preferred mode.
Additionally, the agents can be delivered parenterally, especially
for treatment of retinitis and degenerative retinal diseases, and
for other conditions in Tables I through X, that do not respond to
oral or topical therapy, or for conditions where oral or topical
therapy is not feasible. Parenteral therapy is typically oral,
intraocular, transcutaneous, intradermal, intrathecal,
intramuscular, intra-articular, by inhalation, intravascular,
sublingual, by suppository (e.g. per-rectum or vaginal
application), by inhalation, or other parenteral route.
[0111] A preferred way to practice the invention for dermatological
or ophthalmic disorders in Tables I through X to which this method
is applicable, is to apply the compound of interest, in a cream,
lotion, ointment, or oil based carrier, directly to the lesion.
Typically, the concentration of therapeutic compound in a cream,
lotion, or oil is 0.1 to 2.5%. In general, the preferred route of
administration is oral, topical, intraocular or parenteral. Topical
administration is preferred in treatment of lesions of the skin as
in psoriasis, external eye as in conjunctivitis, keratitis,
scleritis, squamous cell carcinoma, corneal erosion, dry eye
syndrome, and anterior compartment of the eye as in glaucoma,
uveitis and other diseases of the uveal tract, where such direct
application is practical and clinically indicated.
[0112] Oral administration is a preferred alternative for treatment
of other lesions discussed in Tables I through X, where direct
topical application is not useful as in the treatment of chronic or
acute systemic diseases, and diseases of the posterior segment of
the eye, as in retinitis and other retinal degenerative diseases.
Intravascular (intravenous being the preferred route)
administration may be necessary in disorders that cannot be
effectively treated by topical or oral administration.
[0113] Intraocular, transcutaneous, intradermal, intrathecal,
intramuscular, intra-articular injections or other invasive
technique are preferred alternative in cases where the practitioner
wishes to treat one or a few specific areas or lesions depending on
their location within the eye. Usually, the compound is delivered
in an aqueous solution. Additionally, the therapeutic compounds are
injected directly into lesions (intra-lesion administration) in
appropriate cases. Intradermal administration is an alternative for
extraocular lesions. Intra-lesional and intradermal injections are
alternative routes of application for certain lesions, e.g.
extraocular neoplastic or hyperplastic lesions such as squamous
cell carcinoma and condyloma, respectively. Inhalation therapy is
preferred for pulmonary diseases, sublingual and intra-rectal
suppository is preferred for rapid delivery or in clinical
situations where delivery via the oral or intravascular route is
inconvenient or problematic. Application via vaginal topical
formulation or via suppository formulation is preferred for
diseases localized to the vagina or other segment of the urogenital
tract.
[0114] An effective quantity of the compound of interest is
employed in treatment. The dosage of compounds used in accordance
with the invention varies depending on the compound and the
condition being treated. For example, the age, weight, and clinical
condition of the recipient patient; and the experience and judgment
of the clinician or practitioner administering the therapy are
among the factors affecting the selected dosage. Other factors
include: the route of administration, the patient, the patient's
medical history, the severity of the disease process, and the
potency of the particular compound. The dose should be sufficient
to ameliorate symptoms or signs of the disease treated without
producing unacceptable toxicity to the patient.
[0115] In general, an effective amount of the compound is that
which provides either subjective relief of symptoms or an
objectively identifiable improvement as noted by the clinician or
other qualified observer. A typical oral dose is between 1 mg per
day up to 1000-mg per day according to the judgment of the
clinician. Typically, the dosage per day of the compounds of this
invention will depend on the their ability to activate PPARgamma
and their ability to block the angiotensin II type 1 receptor. The
dosages of these compounds will generally run between 0.1 mg to
1000 mg per day with a common dose being 5 mg per day to 300 mg per
day. Typically, the greater the ability to activate PPARgamma and
to block the angiotensin II receptor, the more effective the
compound, and the lower the dosage that is an effective amount.
[0116] An oral dosing schedule is typically, a single dose once a
day. However, more than one dose can be given per day. Because of
the lower incidence of undesirable side effects, the compounds of
this invention can be given until improvement in the disorder of
interest is observed and continued as necessary to maintain such an
improved clinical state. The compounds may or may not be
administered with food or with other agents depending on how food
or other agents affects their absorption by the body and depending
on the judgment of those skilled in the therapeutic art.
[0117] The dosage can be administered once or twice a day, but the
clinician can recommend more or less frequent dosing. Once a
therapeutic result is achieved, the compound can be tapered or
discontinued or continued according to the recommendation of the
clinician. Occasionally, side effects warrant discontinuation of
therapy.
[0118] An effective quantity of the compound of interest is
employed in treatment. The dosage of compounds used in accordance
with the invention varies depending on the compound and the
condition being treated. The age, lean body weight, total weight,
body surface area, and clinical condition of the recipient patient;
and the experience and judgment of the clinician or practitioner
administering the therapy are among the factors affecting the
selected dosage. Other factors include the route of administration
the patient, the patient's medical history, the severity of the
disease process, and the potency of the particular compound. The
dose should be sufficient to ameliorate symptoms or signs of the
disease treated without producing unacceptable toxicity to the
patient.
[0119] Broadly, an oral dosing schedule is from about 0.1 mg to
about 1000 mg once or twice a day. Using telmisartan as the
prototype agent for the purpose of this invention, a convenient
oral dose for an adult patient is approximately 80 mg to 160 mg per
day but could be less or more depending on the indication. A dosage
range for topical treatment is about 0.1% to about 1%
(weight/volume) in a gel, cream or ointment, applied twice a day. A
usual dose for intramuscular or intraocular injection is 0.25 to
2.5 mg, depending on the compartment of the eye to be treated and
on the lean body mass of the patient. A typical dosage for
intra-dermal administration is about 2.5 to 25 mg per injection per
site. A typical dosage for intravenous or intramuscular
administration in an adult patient would be between 50 and 250 mg
per day given in single or divided doses depending on the judgment
of the practitioner.
Compounds and Formulations of the Invention
[0120] Compounds useful for the application of methods described in
this invention include all existing synthetic and naturally
occurring agents that both increase the activity of PPARgamma and
block or antagonize the activity of the angiotensin II type 1
receptor as well as those yet to be discovered that have such dual
ability. Preferred compounds for the purposes of this invention
include telmisartan (Micardis.RTM.), irbesartan (Avapro.RTM.) as
well as any derivatives or formulations thereof and any new ARBs
that may be marketed in the future that have the ability to
activate PPARgamma.
[0121] For oral administration, either solid or fluid unit dosage
forms can be prepared. For preparing solid compositions such as
tablets, the compound of interest is mixed into formulations with
conventional ingredients such as talc, magnesium stearate,
dicalcium phosphate, magnesium aluminum silicate, calcium sulfate,
starch, lactose, acacia, methylcellulose, and functionally similar
materials as pharmaceutical diluents or carriers. Capsules are
prepared by mixing the compound of interest with an inert
pharmaceutical diluent and filling the mixture into a hard gelatin
capsule of appropriate size. Soft gelatin capsules are prepared by
machine encapsulation of a slurry of the compound of interest with
an acceptable vegetable oil, light liquid petrolatum or other inert
oil. Fluid unit dosage forms for oral administration such as
syrups, elixirs and suspensions can be prepared. The water-soluble
forms can be dissolved in an aqueous vehicle together with sugar,
aromatic flavoring agents and preservatives to form a syrup. An
elixir is prepared by using a hydroalcoholic (e.g., ethanol)
vehicle with suitable sweeteners such as sugar and saccharin,
together with an aromatic flavoring agent. Suspensions can be
prepared with an aqueous vehicle with the aid of a suspending agent
such as acacia, tragacanth, methylcellulose and the like.
[0122] Appropriate formulations for parenteral use are apparent to
the practitioner of ordinary skill. Usually, the therapeutic
compound is prepared in an aqueous solution (discussed below) in a
concentration of from about 1 to about 100 mg/ml. More typically,
the concentration is from about 10 to 60 mg/ml or about 20 mg/ml.
Concentrations below 1 mg/ml may be necessary in some cases
depending on the solubility and potency of the compound selected
for use. The formulation, which is sterile, is suitable for various
topical or parenteral routes including sublingual, by suppository
(e.g. per-rectum or vaginal application), oral, intravascular,
intradermal, by inhalation, intramuscular, intra-articular,
intravenous, or other parenteral route.
[0123] In addition to the therapeutic compound, the compositions
may include, depending on the formulation and mode of delivery
desired, pharmaceutically-acceptable, non-toxic carriers or
diluents, which include vehicles commonly used to form
pharmaceutical compositions for animal or human administration. The
diluent is selected so as not to unduly affect the biological
activity of the combination. Examples of such diluents which are
especially useful for injectable formulations are water, the
various saline, organic or inorganic salt solutions, Ringer's
solution, dextrose solution, and Hank's solution. In addition, the
pharmaceutical composition or formulation may include additives
such as other carriers; adjuvants; or nontoxic, nontherapeutic,
nonimmunogenic stabilizers and the like.
[0124] Furthermore, excipients can be included in the formulation.
Examples include cosolvents, surfactants, oils, humectants,
emollients, preservatives, stabilizers and antioxidants. Any
pharmacologically acceptable buffer may be used, e.g., tris or
phosphate buffers. Effective amounts of diluents, additives and
excipients are those amounts which are effective to obtain a
pharmaceutically acceptable formulation in terms of solubility,
biological activity, etc.
[0125] The term "unit dosage form" refers to physically discrete
units suitable as unitary dosages for human subjects and animals,
each unit containing a predetermined quantity of active material
calculated to produce the desired pharmaceutical effect in
association with the required pharmaceutical diluent, carrier or
vehicle. The specifications for the unit dosage forms of this
invention are dictated by and dependent on (a) the unique
characteristics of the active material and the particular effect to
be achieved and (b) the limitations inherent in the art of
compounding such an active material for use in humans and animals.
Examples of unit dosage forms are tablets, capsules, pills, powder
packets, wafers, suppositories, granules, cachets, teaspoonfuls,
tablespoonfuls, dropperfuls, ampoules, vials, aerosols with metered
discharges, segregated multiples of any of the foregoing, and other
forms as herein described.
[0126] Thus, a composition of the invention includes a therapeutic
compound which may be formulated with conventional,
pharmaceutically acceptable, vehicles for topical, oral or
parenteral administration. Formulations may also include small
amounts of adjuvants such as buffers and preservatives to maintain
isotonicity, physiological and pH stability. Means of preparation,
formulation and administration are known to those of skill. See
generally Remington's Pharmaceutical Science 15th ed., Mack
Publishing Co., Easton, Pa. (1980).
[0127] To prepare a topical formulation for the treatment of
ophthalmological or dermatological or other disorders listed in
Tables I through X, a therapeutically effective concentration of
the compound is placed in a dermatological vehicle as is known in
the art. The amount of the therapeutic compound to be administered
and the compound's concentration in the topical formulations depend
upon the vehicle, delivery system or device selected, the clinical
condition of the patient, the side effects and the stability of the
compound in the formulation. Thus, the physician employs the
appropriate preparation containing the appropriate concentration of
the therapeutic compound and selects the amount of formulation
administered, depending upon clinical experience with the patient
in question or with similar patients.
[0128] The therapeutic compound is optionally administered
topically by the use of a transdermal therapeutic system (see
Barry, Dermatological Formulations, (1983) p. 181 and literature
cited therein). While such topical delivery systems have been
designed largely for transdermal administration of low molecular
weight drugs, by definition they are capable of percutaneous
delivery. They may be readily adapted to administration of the
therapeutic compounds of the invention by appropriate selection of
the rate-controlling microporous membrane.
[0129] For ophthalmic applications the therapeutic compound is
formulated into solutions, suspensions, and ointments appropriate
for use in the eye. The concentrations are usually as discussed
above for topico-local preparations. For ophthalmic formulations,
see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker,
Inc., New York, N.Y. (1993) and also Havener, W. H., Ophthalmic
Pharmacology, C.V. Mosby Co., St. Louis (1983).
[0130] The concentration of the therapeutic compound used depends
on the mode of delivery. For topical ophthalmic and extraocular
formulations, the concentration of the therapeutic compound is in
the range of about 0.01% weight/weight (w/w) to about 10% w/w.
Typically, the concentration of the therapeutic compound for this
mode of delivery is in the range of about 0.025% w/w to about 2.5%
w/w. Solid dispersions of the therapeutic compound as well as
solubilized preparations can be used. For intraocular formulations
(chemical delivery or delivery by invasive device), the therapeutic
compound is delivered at a concentration high enough to achieve a
final concentration in the range of about 0.1:mol/L to about 10
mol/L within the target ophthalmic compartment (e.g. the posterior
chamber for the treatment of retinal diseases). Typically, for this
mode of delivery, the final concentration of the therapeutic
compound is in the range of about 0.25:mol/L to about 5:mol/L.
Solid dispersions of the therapeutic compound as well as
solubilized preparations can be used. Thus, the precise
concentration is subject to modest but not undue experimental
manipulation well within the skill of the ordinary medical
practitioner in order to optimize the therapeutic response.
Suitable vehicles include oil-in-water or water-in-oil emulsions
for preparation of ointments using mineral oils, petrolatum,
lanolin, glycerin and the like as well as gels such as hydrogel. A
preferred embodiment of the present invention involves
administration of semi-solid or solid implants containing PPARgamma
agonists.
[0131] Slow or extended-release delivery systems, including any of
a number of biopolymers (biological-based systems), systems
employing liposomes, colloids, resins, and other polymeric delivery
systems or compartmentalized reservoirs, can be utilized with the
compositions described herein to provide a continuous or long term
source of therapeutic compound. Such slow release systems are
applicable to formulations for delivery via topical, intraocular,
oral, and parenteral routes.
[0132] As mentioned above, delivery intravascularly,
intra-articularly, intramuscularly, intra-articularly,
intradermally, or other parenteral route can be accomplished by
injection, cannula or other invasive device designed to introduce
precisely metered amounts of a desired formulation to a particular
compartment or tissue. For example, delivery to certain areas
within the eye, in situ, can be accomplished by injection, cannula
or other invasive device designed to introduce precisely metered
amounts directly or contained in a reservoir for slow release in
situ, of a desired formulation to a particular compartment or
tissue within the eye (e.g. anterior or posterior chamber, uvea or
retina). Preferably, a solid or semisolid implant can be delivered
subretinally using the instrumentation and methods described in
U.S. Pat. No. 5,817,075 and U.S. Pat. No. 5,868,728.
Combination Use of Drugs
[0133] A compound according to the present invention may be used in
combination with a diabetes mellitus-treating agent, a diabetic
complication-treating agent, an antihyperlipemic agent, a
hypotensive or antihypertensive agent, an anti-obesity agent, a
diuretic, a chemotherapeutic agent, an immunotherapeutic agent, and
immunosuppressive agent, and the like (hereinafter referred to as a
concomitant agent). In such case, the periods of the treatments
with a compound according to the present invention and with a
concomitant agent are not limited particularly, and such agents may
given to a patient simultaneously or at a certain time interval.
The dose of a concomitant drug may appropriately be determined
based on the customary clinical dose. The ratio between a compound
according to the present invention and a concomitant agent may be
appropriately determined based on various factors such as the
subject to be treated, the administration route, the disease or the
condition to be treated and the combination of the drugs. For
example, when a human is treated, 1 parts by weight of a compound
according to the present invention is combined with 0.01 to 100
parts by weight of a concomitant agent.
[0134] Examples of an agent for treating diabetes mellitus are an
insulin formulation (e.g., animal insulin formulations extracted
from a pancreas of a cattle or a swine; a human insulin formulation
synthesized by a gene engineering technology using microrganisms or
methods), an insulin sensitivity enhancing agent (e.g.,
pioglitazone hydrochloride, troglitazone, rosiglitazone and the
like), an alpha-glycosidase inhibitor (e.g., voglibose, acarbose,
miglitol, emiglitate and the like), a biguanide (e.g., phenformin,
metformin, buformin and the like), or a sulfonylurea (e.g.,
tolbutamide, glib enclamide, gliclazide, chlorpropamide,
tolazamide, acetohexamide, glyclopyramide, glimepiride and the
like) as well as other insulin secretion-promoting agents (e.g.,
repaglinide, senaglinide, nateglinide, mitiglinide, GLP-1 and the
like), amyrin agonist (e.g. pramlintide and the like),
phosphotyrosinphosphatase inhibitor (e.g. vanadic acid and the
like) and the like.
[0135] Examples of an agent for treating diabetic complications are
an aldose reductase inhibitor (e.g., tolrestat, epalrestat,
zenarestat, zopolrestat, minalrestat, fidareatat, SK-860, CT-112
and the like), a neurotrophic factor (e.g., NGF, NT-3, BDNF and the
like), PKC inhibitor (e.g. LY-333531 and the like), AGE inhibitor
(e.g. ALT946, pimagedine, pyradoxamine, phenacylthiazolium bromide
(ALT766) and the like), an active oxygen quenching agent (e.g.,
thioctic acid or derivative thereof, a bioflavonoid including
flavones, isoflavones, flavonones, procyanidins, anthocyanidins,
pycnogenol, lutein, lycopene, vitamins E, coenzymes Q, and the
like), a cerebrovascular dilating agent (e.g., tiapride, mexiletene
and the like).
[0136] An antihyperlipemic agent may for example be a statin-based
compounds which is a cholesterol synthesis inhibitor (e.g.,
pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin,
rosuvastatin and the like), a squalene synthetase inhibitor or a
fibrate compound having a triglyceride-lowering effect (e.g.,
gemfibrozil, bezafibrate, clofibrate, sinfibrate, clinofibrate and
the like).
[0137] A hypotensive agent may for example be a n angiotensin
converting enzyme inhibitor (e.g., captopril, enalapril, delapril,
benazepril, cilazapril, enalapril, enalaprilat, fosinopril,
lisinopril, moexipril, perindopril, quinapril, ramipril,
trandolapril, and the like) or an angiotensin II antagonist (e.g.,
losartan, candesartan cilexetil, eprosartan, valsartan,
telmisartan, irbesartan, tasosartan and the like).
[0138] An antiobesity agent may for example be a central
antiobesity agent (e.g., dexfenfluramine, fenfluramine,
phentermine, sibutramine, amfepramone, dexamphetamine, mazindol,
phenylpropanolamine, clobenzorex and the like), a pancreatic lipase
inhibitor (e.g., orlistat and the like), .beta.-3 agonist (e.g.,
CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085
and the like), a peptide-based appetiie-suppressing agent (e.g.,
leptin, CNTF and the like), a cholecystokinin agonist (e.g.,
lintitript, FPL-15849 and the like) and the like.
[0139] A diuretic may for example be a xanthine derivative (e.g.,
theobromine sodium salicylate, theobromine calcium salicylate and
the like), a thiazide formulation (e.g., ethiazide,
cyclopenthiazide, trichloromethiazide, hydrochlorothiazide,
hydroflumethiazide, bentylhydrochlorothiazide, penflutizide,
polythiazide, methyclothiazide and the like), anti-aldosterone
formulation (e.g., spironolactone, triamterene and the like), a
decarboxylase inhibitor (e.g., acetazolamide and the like), a
chlorbenzenesulfonamide formulation (e.g., chlorthalidone,
mefruside, indapamide and the like), azosemide, isosorbide,
ethacrynic acid, piretanide, bumetanide, furosemide and the
like.
[0140] A chemotherapeutic agent may for example be an alkylating
agent (e.g., cyclophosphamide, iphosphamide and the like), a
metabolism antagonist (e.g., methotrexate, 5-fluorouracil and the
like), an anticancer antibiotic (e.g., mitomycin, adriamycin and
the like), a vegetable-derived anticancer agent (e.g., vincristine,
vindesine, taxol and the like), cisplatin, carboplatin, etoposide
and the like. Among these substances, 5-fluorouracil derivatives
such as furtulon and neofurtulon are preferred.
[0141] An immunotherapeutic agent may for example be a
microorganism or bacterial component (e.g., muramyl dipeptide
derivative, picibanil and the like), a polysaccharide having immune
potentiating activity (e.g., lentinan, sizofilan, krestin and the
like), a cytokine obtained by a gene engineering technology (e.g.,
interferon, interleukin (IL) and the like), a colony stimulating
factor (e.g., granulocyte colony stimulating factor, erythropoetin
and the like) and the like, among these substances, those preferred
are IL-1, IL-2, IL-12 and the like.
[0142] An immunosuppressive agent may for example be a calcineurin
inhibitor/immunophilin modulator such as cyclosporine (Sandimmune,
Gengraf, Neoral), tacrolimus (Prograf, FK506), ASM 981, sirolimus
(RAPA, rapamycin, Rapamune), or its derivative SDZ-RAD, a
glucocorticoid (prednisone, prednisolone, methylprednisolone,
dexamethasone and the like), a purine synthesis inhibitor
(mycophenolate mofetil, MMF, CellCept.RTM., azathioprine,
cyclophosphamide), an interleukin antagonist (basiliximab,
daclizumab, deoxyspergualin), a lymphocyte-depleting agent such as
antithymocyte globulin (Thymoglobulin, Lymphoglobuline), anti-CD3
antibody (OKT3), and the like.
[0143] In addition, an agent whose cachexia improving effect has
been established in an animal model or at a clinical stage, such as
a cyclooxygenase inhibitor (e.g., indomethacin and the like)
[Cancer Research, Vol. 49, page 5935-5939, 1989], a progesterone
derivative (e.g., megestrol acetate) [Journal of Clinical Oncology,
Vol. 12, page 213-225, 1994], a glucosteroid (e.g., dexamethasone
and the like), a metoclopramide-based agent, a
tetrahydrocannabinol-based agent (supra), a lipid metabolism
improving agent (e.g., eicosapentanoic acid and the like) [British
Journal of Cancer, Vol. 68, page 314-318, 1993], a growth hormone,
IGF-1, or an antibody against TNF-.alpha., LIF, IL-6, oncostatin M
which are cachexia-inducing factors may also be employed
concomitantly with a compound according to the present
invention.
[0144] The possible preferred combinations of the agents for the
prevention and/or treatment of diabetes are, a PPARgamma activator
with ARB activity, and:
1) an insulin formulation and a biguanide;
2) a sulfonylurea agent and a biguanide;
3) a sulfonylurea agent and an alpha-glycosidase inhibitor;
4) a biguanide and an alpha-glycosidase inhibitor;
5) a blood sugar reducing agent and the other kind of agents for
treating diabetic complications;
6) an 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase
inhibitor;
7) any other two kinds of agents mentioned above.
8) an agent that inhibits activity of angiotensin converting
enzyme
[0145] In case that the compound or the composition of the present
invention is used in combination with the other agent, an amount of
each other agent can be reduced in a range which is safe in light
of its adverse effect. Especially, an insulin sensitivity enhancing
agent, a biguanide and a sulfonylurea agent can be used in less
dose than regular dose so that adverse effects which may be caused
by these agents can be safely avoided. In addition, an agent for
treating diabetic complications, an antihyperlipemic agent and a
hypotensive agent can also be used in less dose, so that adverse
effect which may be caused by them can be avoided effectively.
[0146] As noted above, by administering both an ARB and a PPAR
activator formulated together in a single pill or tablet, one can
also treat glucose intolerance or type 2 diabetes and other PPAR
responsive disorders without causing fluid retention, edema, or
congestive heart failure. For this purpose, one can prepare and use
a pharmaceutical composition comprising: (i) a PPAR activator in a
therapeutically effective amount sufficient to prophylactically
prevent, slow, delay or treat a metabolic, inflammatory, atopic,
autoimmune, proliferative, or cardiovascular disorder in humans;
(ii) an angiotensin II type 1 receptor antagonist in a
therapeutically effective amount sufficient to prevent, slow,
delay, or treat fluid retention, peripheral edema, pulmonary edema,
or congestive heart failure; and (iii) a pharmaceutically
acceptable carrier. For this purpose, the PPAR activator in the
pharmaceutical composition can be is a thiazolidinedione selected
from the group of compounds consisting of rosiglitazone,
pioglitazone, KRP 297, MCC-555, netoglitazone, rivoglitazone and
balagitazone, or an analog thereof, or a tautomeric form thereof,
or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof. Alternatively, the
PPAR activator in the pharmaceutical composition can be a
non-thiazolidinedione selected from the group of compounds
consisting of tesaglitazar, farglitazar, ragaglitazar, LY818, T131,
LSN862, DRF 4832, LM 4156, LY 510929, LY 519818, TY 51501, X 334,
or an analog thereof, or a tautomeric form thereof, or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate thereof. Other thiazolidinedione or
non-thiazolidinedione activators of PPARs that are familiar to
those skilled in the art can also be employed. For purposes of
making the pharmaceutical composition, the angiotensin II type 1
receptor antagonist can be a compound selected from the group
consisting of telmisartan, irbesartan, valsartan, losartan,
candesartan, candesartan cilexetil, olmesartan, olmesartan
medoximil, losartan, valsartan, eprosartan, irbesartan, tasosartan,
pomisartan, ripisartan, and forasartan, or an analog thereof, or a
tautomeric form thereof, or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate thereof.
[0147] The compounds in this invention can also be given orally in
combination with natural or synthetic compounds that bind to or
modify the activity of the vitamin D receptor or other nuclear
hormone receptor or in combination with compounds that bind to or
modify the activity of the retinoid X receptor to provide for a
synergistic effect in the treatment or prevention of the disorders
listed in Tables I through X. Examples of such compounds that
provide for synergistic effect when given in combination with the
drugs encompassed by the current invention include vitamin D
analogs, various retinoic acid derivatives, and other ligands for
retinoid X receptors or retinoic acid receptors including but not
limited to compounds such as LG100268, tazarotene, TTNPB, AGN
190121, adapalene or LGD1069 (Targretin).
[0148] Synergistic therapeutic effects can be achieved by oral or
topical administration of the drugs encompassed in the current
invention together with orally, topically or intravenously
administered drugs that bind to and modify the activity of either
the vitamin D receptor, the glucocorticoid receptor, the
intracellular enzyme calcineurin, the retinoid X receptors, the
retinoic acid receptors, or other PPARs such as PPARalpha or
PPARdelta. A preferred dosage range for administration of a
retinoic acid derivative or retinoid would typically be from 0.1 to
100 mg per square-meter of body surface area, depending on the
drug's ability to bind to or modify the activity of its cognate
nuclear receptor, given in single or divided doses, orally or by
continuous infusion, two or three times per day. For synergistic
therapy, the preferred dosages and routes and frequency of
administration of the vitamin D analogs or retinoid compounds can
be similar to the dosages and routes and frequency of
administration ordinarily recommended for these agents when given
without PPAR activators. Examples of effective retinoids are
9-cis-retinoic acid, 13-cis-retinoic acid, all-trans-retinoic acid
(at-RA). Preferred retinoids for this purpose would include
13-cis-retinoic acid, tazarotene, or Targretin. A preferred dosage
range for systemic administration of a vitamin D analog would
typically be from 0.1 to 100 mg per square-meter of body surface
area, depending on the drug's ability to bind to and or activate
its cognate vitamin D receptor, given in single or divided doses,
orally or by continuous infusion, two or three times per day.
Examples of effective vitamin D analogs are 1,25-dihydroxy-vitamin
D, calcipotriene and calcipotriol. The dosage range and routes and
frequency of administration of PPAR activators required to achieve
synergistic effects when given with vitamin D or retinoid
derivatives are the same as those described elsewhere in this
disclosure. The preferred mode of administration of these drugs for
synergistic therapeutic purposes would be orally although
alternatively one can use topical or parenteral routes of
administration. The dosages and the modes and frequency of
administration of the vitamin D or retinoid related compounds for
synergistic topical therapy would be similar to those ordinarily
recommended for these agents when given without PPAR activators.
The dosage range and the modes and frequency required for topical
administration of the flavonoid thiazolidine derivatives given in
combination with vitamin D or retinoid related compounds are the
same as those described elsewhere in this disclosure.
[0149] Synergistic therapeutic effects can be achieved by oral or
topical administration of the drugs encompassed in the current
invention together with orally, topically or intravenously
administered natural or synthetic antioxidants. These include
ascorbic acid and its derivatives (e.g. vitamin C), the tocopherols
(e.g. vitamin E, vitamin E succinate), carotenes and carotenoids
(e.g. .beta.-carotene), alpha-lipoic acid, probucols, flavones,
isoflavones and flavonols (e.g. quercetin, genistein, catechin,
apigenin, lutein, luteolin), lycopene, pycnogenol, glutathione and
its derivatives (e.g. N-acetylcysteine and dithiothreitol), and
phytoestrogens and phenolic anthocyanidin and procyanidin
derivatives (e.g. resveratrol, cyanidin, cinnamic acid).
[0150] The compounds of the instant invention are further useful to
suppress the mediators of neurogenic inflammation (e.g. substance P
or the tachykinins), and may be used in the treatment of rheumatoid
arthritis; psoriasis; topical inflammation such as is associated
with sunburn, eczema, or other sources of itching; and allergies,
including asthma. The compounds can also function as
neuromodulators in the central nervous system, with useful
applications in the treatment of Alzheimer's disease and other
forms of dementia, pain (as a spinal analgesic), and headaches.
Furthermore, in disorders involving myocardial fibrosis, myocardial
ischemia, pathological conditions secondary to the autoimmune
response to allograft transplantation, the splanchnic blood flow,
including hepatic fibrosis, cirrhosis and esophageal varices, the
compounds of the invention can provide cytoprotection.
[0151] The present invention is further detailed in the following
Examples and Methods which are not intended to restrict the present
invention.
Method for Designing and Identifying an ARB as a PPAR Ligand
[0152] ARBs, or derivatives thereof, may be tested for their
ability to activate the various PPAR isoforms by utilizing standard
screening methods known to those skilled in the art including but
not limited to cell based transactivation assays or cell free
assays that test the ability of a compound to activate a PPAR
construct by measuring the output of a reporter signal that
reflects the extent of the PPAR activation. For example, the
angiotensin receptor blocker telmisartan is added to the culture
media of CV1 cells or other cells that can be transfected with a
full length or partial PPAR cDNA sequence together with a reporter
construct containing a PPAR response element or other appropriate
response element fused to a reporter gene such as luciferase. The
ability of telmisartan to activate PPARgamma is tested by measuring
the luciferase reporter gene activity and it is found that
telmisartan causes a significant increase in reporter gene activity
well above the background level present in the cells not treated
with telmisartan. Similar experiments are performed with irbesartan
which is also found to activate PPARgamma. Any ARBs found to
activate PPARgamma according to these or other methods can be used
to treat disorders known to be responsive to PPAR activators.
[0153] One can also make chemical modifications to existing ARBs
that can be predicted to enhance their ability to activate
PPARgamma. Therefore, one can design ARBs that are particularly
effective in treating disorders known to be responsive to PPAR
activators without causing fluid retention, edema, or congestive
heart failure. One can also modify chemical structures of PPAR
activators to enhance their ability to inhibit ACE activity or
block angiotensin receptors. This can be accomplished using
published information on the crystal structures of the PPARs and
published information on the amino acid residues and regions of the
PPARs that are important in receptor activation together with known
methods for testing ability of compounds to inhibit ACE activity or
block angiotensin receptors. Using methods known to those skilled
in the art, one can make chemical modifications to existing ARBs or
ACE inhibitors or design derivatives thereof that can be predicted
to have improved ability to activate PPARs than existing ARBs or
ACE inhibitors.
Method of Identifying a PPAR Ligand with Decreased Risk for Causing
Fluid Retention, Edema, or Congestive Heart Failure
[0154] One can identify PPARgamma activators that have improved
safety profile and decreased risk for causing fluid retention,
edema, or congestive heart failure by testing their ability to
inhibit angiotensin converting enzyme activity or their ability to
block the angiotensin receptor. PPARgamma ligands or PPARgamma
activators that also inhibit ACE activity or block angiotensin II
type 1 receptors represent an improvement over existing PPAR
ligands for treating PPAR responsive disorders because they have
reduced likelihood of causing fluid retention, edema, or congestive
heart failure. A variety of assays are available that can be used
by those skilled in the art to determine whether a PPARgamma
activator can also block the angiotensin II type 1 receptor or
inhibit the activity of angiotensin converting enzyme. According to
the method of Groff J L, et al. (Simplified enzymatic assay of
angiotensin-converting enzyme in serum. Clin Chem. 1993; 39:400-4)
or other assays that are familiar to those skilled in the art of
testing compounds for their ability to inhibit angiotensin
converting enzyme activity.
[0155] The ability of a PPAR ligand to selectively block the
interaction of angiotensin II (AII) with the angiotensin II type 1
receptor can be determined by the method of competitive binding of
radiolabelled angiotensin II to preparations enriched in the AII
type 1 receptor vs. the AII type 2 receptor. Other methods that are
familiar to those skilled in the art of identifying compounds that
block the angiotensin II type 1 receptor can also be used to
determine whether a PPAR activator can block the angiotensin II
type 1 receptor to any degree which would be useful in identifying
a PPAR activator that is unlikely to cause fluid retention, edema,
or congestive heart failure.
EXAMPLES
[0156] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the present invention, and are
not intended to limit the scope of what the inventors regard as
their invention nor are they intended to represent that the
experiments below are all and only experiments performed. Efforts
have been made to ensure accuracy with respect to numbers used
(e.g. amounts, temperature, etc.) but some experimental errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Celsius, and pressure
is at or near atmospheric.
Example 1
Identification of Angiotensin II Type 1 Receptor Blockers That
Activate PPARgamma
[0157] PPAR.gamma. activity was determined by transactivation
assays in CV-1 cells (CCL-70 line from ATCC, Bethesda, Md.)
transfected using the GenePorter transfection reagent (Gene Therapy
Systems, San Diego, Calif.) to deliver 200 ng of a PPAR.gamma.
expression plasmid and 1 .mu.g of a luciferase reporter plasmid and
400 ng pCMVSport .beta.-gal (Gibco, Grand Island, N.J.) as an
internal control. 24 hr post-transfection, cells were treated with
varying concentrations of the test compounds (telmisartan,
irbesartan, valsartan, losartan, the active metabolite of losartan,
the active forms of candesartan and olmesartan, rosiglitazone, or
pioglitazone) and incubated for an additional 24 hr. Cell extracts
were assayed for luciferase and .beta.-galactosidase activity using
Promega (Madison, Wis.) assay systems. All treatments were
performed in triplicate, and normalized for .beta.-galactosidase
activity. Agonist concentrations yielding half maximal activation
(EC.sub.50 values) were calculated using GraphPad Prism version
3.03 (GraphPad Software, Inc., San Diego, Calif.).
[0158] Telmisartan significantly activated PPAR.gamma. (5-8 fold)
when tested at concentrations (1-5 .mu.M) that can be achieved in
plasma with conventional oral dosing [Stangier, 2000 #14424].
Telmisartan functioned as a moderately potent (EC.sub.50=5.6
.mu.M), PPAR.gamma. agonist, activating the receptor to 25%-30% of
the maximum level of activity achieved by the full agonists
pioglitazone and rosiglitazone. Irbesartan activated PPAR.gamma.
(2-3 fold activation) when tested at 10 .mu.M. None of the other
ARBs tested caused any significant activation of PPAR even when
tested at higher concentrations (more than 10 .mu.M). These
experiments demonstrate that two known angiotensin receptor
blockers, telmisartan and irbesartan, are also activators of
PPARgamma. Because PPARgamma activators can be used to treat and
prevent type 2 diabetes, the metabolic syndrome, and other clinical
disorders responsive to treatment with PPAR activators, these
experiments demonstrate the utility of telmisartan and irbesartan
for the prevention and treatment of type 2 diabetes, the metabolic
syndrome, and other disorders known to be responsive to treatment
with PPAR activators.
Example 2
Measurement of In Vitro Adipocyte Differentiation Activity
[0159] The following examples 2 and 3 provide a generic means to
measure adipocyte differentation to determine if one has an
insulin-sensitizing agent. A mouse preadipocyte cell line (3T3-L1)
obtained from the American Type Culture Collection, and the cells
are grown in a Dulbecco's modified Eagle medium (DMEM) containing
4.5 g/L glucose, 50 mg/L streptomycin sulfate, 100,000 units/L
penicillin-G, 0.584 g/L L-glutamine, 4 mg/L pantothenate, 8 mg/L
D-biotin, and 10 mM HEPES (pH 7.2)] supplemented with 10% fetal
bovine serum (FBS). The cells are then plated at
1.5.times.104/cm.sup.2 in a 96-well tissue culture plate (view
plate, 96 white, Packard) coated with type 1 collagen. After the
cells had reached confluence, the cells were further cultured with
differentiation medium DMEM supplemented with 5% FBS, 100 ng/mL
insulin, 0.1 mM isobutylmethylxanthine (IBMX), and 1 mM
dexamethasone, and containing various concentrations of compounds
for 4 days. The compounds added from a stock solution of dimethyl
sulfoxide (DMSO). The final concentration of DMSO in the
differentiation medium does not exceed 0.1% (v/v). DMSO (0.1%) was
added to the control cultures. The medium was replaced with
maintenance medium (DMEM supplemented with 5% of FBS and 100 ng/mL
of insulin), and the cells cultured for 2 more days. Activity of
stimulation of adipogenesis was determined by exposure of the cells
to [14-C]-acetic acid (7.4 kBq/mL), and uptake of [14-C]-acetic
acid monitored after 1 h of incubation. The medium is discarded and
the cells washed twice with phosphate-buffered saline. The cells
are air-dried, and 200 mL of scintillation cocktail (Microscint-20,
Packard) added to the wells, and counted with a Packard TopCount
microplate scintillation counter. Stimulation of adipogenesis is
expressed as concentrations equivalent to the [14-C] label uptake
counts in the treatment with 10 uM telmisartan.
Example 3
Measurement of In Vivo Insulin-Sensitivity Activity
[0160] The hypoglycemic activity of the test compounds in insulin
resistant obese fatty (fa/fa) Zucker rats (Jackson Laboratory, Bar
Harbor, Me.). These rats are profoundly insulin resistant with
extremely high blood concentrations of insulin. Lean littermates
(-/-) are used as controls. Each test compounds is administered to
three Zucker rats at 10 mg/kg daily for five days after which blood
samples are taken in the non-fasting state. Blood samples are
collected, placed in a hematocrit centrifuge tube, and centrifuged
to obtain plasma. Insulin in the collected plasma is measured by
means of a radioimmuno-assay kit (Linco Research, Inc, St Charles,
Mo.). The insulin-sensitizing activity of the test compounds are
calculated as follows: Insulin-sensitivity activity (%)=[(PI in
C-PI in T)/PI in C].times.100 [0161] where "PI in C" is plasma
insulin in control rats and "PI in T" is plasma insulin in rats
treated with test compounds.
Example 4
A Clinical Trial Using a PPARgamma Activator to Treat Type 2
Diabetes without Causing Fluid Retention, Edema, or Heart
Failure
[0162] A 49 year old female with hypertension,
hypertriglyceridemia, and type 2 diabetes was selected for therapy.
Before administration of telmisartan, the patient had a blood
pressure of 160/90 mmHg, fasting serum glucose of 183 mg/dl, a
fasting serum triglyceride level of 264 mg/dl, and an HDL
cholesterol level of 48 mg/dl. The patient is taking another
medication for type 2 diabetes but the dose of this medication is
held constant throughout the trial. The patient is given
telmisartan (Micardis.RTM.) at an oral dose of 80 mg/day. After
three weeks of telmisartan therapy, the blood pressure is reduced
to 143/91 mmHg with little or no improvement in fasting glucose
(188 mg/dl), triglyceride (281 mg/dl), or HDL cholesterol levels
(50 mg/dl). The oral dose of telmisartan (Micardis.RTM. is then
increased to 160 mg/day. After seven weeks of telmisartan
(Micardis.RTM.) therapy at 160 mg/day, the patient's blood pressure
is reduced to 131/81 mmHg and there is a significant improvement in
the diabetes with the glucose level reduced to 145 mg/dl, the
triglyceride level reduced to 178 mg/dl, and the HDL cholesterol
increased to 60 mg/dl. Clinical examination reveals no evidence of
any increase in fluid retention, peripheral edema, pulmonary edema,
or congestive heart failure. The telmisartan (Micardis.RTM.)
therapy is continued according to the judgment of the clinician in
order to maintain the improved control of the patient's blood
pressure and her type 2 diabetes.
Example 5
A Clinical Trial Using a PPARgamma Activator to Treat the Metabolic
Syndrome Without Causing Fluid Retention, Edema, or Heart
Failure
[0163] A 59 year old female with the metabolic syndrome was
selected for therapy. Before administration of telmisartan, the
patient had a blood pressure of 160/79 mmHg, fasting serum glucose
of 118 mg/dl, fasting insulin level of 15 microunits/ml, fasting
triglycerides of 129 mg/dl, and waist girth of 120 cm. The patient
has the metabolic syndrome as defined by the National Cholesterol
Education Program. The metabolic syndrome is associated with a 5-9
fold increase in the risk for developing type 2 diabetes and a 2-3
fold increase risk in cardiovascular mortality. The patient is
given telmisartan (Micardis.RTM.) at an oral dose of 80 mg/day for
treatment of the metabolic syndrome. After two weeks of telmisartan
therapy, the patient no longer meets the diagnostic criteria of the
metabolic syndrome and her blood pressure is reduced to 130/69
mmHg, the fasting glucose is normalized to 105 mg/dl, and the
fasting triglyceride level is reduced to 115 mg/dl. Clinical
examination reveals no evidence of any increase in fluid retention,
peripheral edema, pulmonary edema, or congestive heart failure. The
telmisartan (Micardis.RTM.) therapy is continued according to the
judgment of the clinician in order to prevent recurrence of the
metabolic syndrome and prevent development of type 2 diabetes.
Example 6
A Clinical Trial Using a PPARgamma Activator to Treat Inflammation
Without Causing Fluid Retention, Edema or Heart Failure
[0164] A 57 year old female with osteoarthritis and inflammation as
judged by elevated C-reactive protein (CRP) levels was selected for
therapy. Before administration of telmisartan, the patient had a
markedly increased serum CRP level of 7.9 mg/L indicative of active
inflammation. The patient is given telmisartan (Micardis.RTM.) at
an oral dose of 80 mg/day. After 6 weeks of telmisartan therapy,
the CRP level is reduced to 4.1 mg/L. After 9 weeks of therapy, the
CRP level remains reduced at 3.9 mg/L and symptoms of inflammation
and osteoarthritis are stabilized. Clinical examination reveals no
evidence of any increase in fluid retention, peripheral edema,
pulmonary edema, or congestive heart failure. The telmisartan
(Micardis.RTM.) therapy is continued according to the judgment of
the clinician in order to maintain the improved control of the
inflammation.
REFERENCES
Examples of ARBs Encompassed by this Invention
[0165] 1. Maillard M P, Wurzner G, Nussberger J, Centeno C, Burnier
M, Brunner H R. Comparative angiotensin II receptor blockade in
healthy volunteers: the importance of dosing. Clin Pharmacol Ther.
2002; 71:68-76. [0166] 2. Almansa C, et al. Synthesis and
structure-activity relationship of a new series of potent AT 1
selective angiotensin II receptor antagonists:
5-(biphenyl-4-ylmethyl)pyrazoles. J Med. Chem. 1997; 40:547-58.
[0167] 3. Almansa C, et al. Diphenylpropionic acids as new AT1
selective angiotensin II antagonists. J Med. Chem. 1996;
39:2197-206. [0168] 4. Le Bourdonnec B, et al. Synthesis and
pharmacological evaluation of new pyrazolidine-3,5-diones as AT1
receptor antagonists. J Med. Chem. 2000; 43:2685-97. [0169] 5.
Almansa C, et al. Diphenylpropionic acids as new AT1 selective
angiotensin II antagonists. J Med. Chem. 1996; 39:2197-206. [0170]
6. Norman N H, et al. 4-(Heteroarylthio)-2-biphenylyltetrazoles as
nonpeptide angiotensin II antagonists. J Med. Chem. 1995;
38:4670-8. [0171] 7. Mederski W W, et al. Non-peptide angiotensin
II receptor antagonists: synthesis and biological activity of a
series of novel 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine
derivatives. J Med. Chem. 1994; 37:1632-45. [0172] 8. Dhanoa D S,
et al. (Dipropylphenoxy)phenylacetic acids: a new generation of
nonpeptide angiotensin II receptor antagonists. J Med. Chem. 1993;
36:3738-42. [0173] 9. Bernhart C A, et al. A new series of
imidazolones: highly specific and potent nonpeptide AT1 angiotensin
II receptor antagonists. J Med. Chem. 1993; 36:3371-80. [0174] 10.
Atwal K S, et al. Dihydropyrimidine angiotensin II receptor
antagonists. J Med. Chem. 1992; 35:4751-63. [0175] 11. Lin H S, et
al. Nonpeptide angiotensin II receptor antagonists: synthetic and
computational chemistry of
N-[[4-[2-(2H-tetrazol-5-yl)-1-cycloalken-1-yl]phenyl]methyl]imidazole
derivatives and their in vitro activity. J Med. Chem. 1992;
35:2658-67. [0176] 12. Blankley C J, et al. Synthesis and
structure-activity relationships of a novel series of non-peptide
angiotensin II receptor binding inhibitors specific for the AT2
subtype. J Med. Chem. 1991; 34:3248-60. [0177] 13. Buhlmayer P, et
al. Nonpeptidic angiotensin II antagonists: synthesis and in vitro
activity of a series of novel naphthalene and tetrahydronaphthalene
derivatives. J Med. Chem. 1991; 34:3105-14. [0178] 14. Schmidt B,
Schieffer B. Angiotensin II AT1 Receptor Antagonists. Clinical
Implications of Active Metabolites. J Med. Chem. 2003; 46:2261-70.
[0179] 15. Le Bourdonnec B, et al. Comparison of 3D structures and
AT(1) binding properties of pyrazolidine-3,5-diones and
tetrahydropyridazine-3,6-diones with parent antihypertensive drug
irbesartan. J Med. Chem. 2002; 45:4794-8. [0180] 16. Ellingboe J W,
et al. Metabolites of the angiotensin II antagonist tasosartan: the
importance of a second acidic group. J Med. Chem. 1998; 41:4251-60.
[0181] 17. Ashton W H, et al. Triazolinone biphenylsulfonamide
derivatives as orally active angiotensin II antagonists with potent
AT1 receptor affinity and enhanced AT2 affinity. J Med. Chem. 1994;
37:2808-24. [0182] 18. Kubo K, et al. Nonpeptide angiotensin II
receptor antagonists. Synthesis and biological activity of
benzimidazoles. J Med. Chem. 1993; 36:1772-84. [0183] 19. De B, et
al. Discovery of a novel class of orally active, non-peptide
angiotensin II antagonists. J Med. Chem. 1992; 35:3714-7. [0184]
20. Carini D J, et al Nonpeptide angiotensin II receptor
antagonists: the discovery of a series of
N-(biphenylylmethyl)imidazoles as potent, orally active
antihypertensives. J Med. Chem. 1991; 34:2525-47. Examples of
Insulin-Sensitizing Agents with Functionalities that can be Used to
Derivitize ARBs [0185] 21. Brooks D A, Etgen G J, Rito C J, et al.
Design and synthesis of
2-methyl-2-[4-(2-[5-methyl-2-aryloxazol-4-yl]ethoxy)phenoxy]propionic
acids: a new class of dual PPARalpha/gamma agonists. J Med. Chem.
2001; 44:2061-4. [0186] 22. Henke B R, Blanchard S G, Brackeen M F,
et al. N-(2-Benzoylphenyl)-L-tyrosine PPAR.gamma. agonists. 1.
Discovery of a novel series of potent antihyperglycemic and
antihyperlipidemic agents. J Med. Chem. 1998; 41:5020-36. [0187]
23. Cronet P, Petersen J F, Folmer R, et al. Structure of the
PPAR.alpha. and -gamma ligand binding domain in complex with AZ
242; ligand selectivity and agonist activation in the PPAR family.
Structure (Camb). 2001; 9:699-706. Anti-Inflammatory Effects of
ARBs [0188] 24. Wang N, et al. Constitutive activation of
peroxisome proliferator-activated receptor-gamma suppresses
pro-inflammatory adhesion molecules in human vascular endothelial
cells. J Biol. Chem. 2002; 277:34176-81. [0189] 25. Brasier A R, et
al. Angiotensin II induces gene transcription through
cell-type-dependent effects on the nuclear factor-kappaB
(NF-kappaB) transcription factor. Mol Cell Biochem. 2000;
212:155-69. [0190] 26. Miyajima A, et al. Angiotensin II type I
antagonist prevents pulmonary metastasis of murine renal cancer by
inhibiting tumor angiogenesis. Cancer Res. 2002; 62:4176-9. [0191]
27. Phillips M I, Kagiyama S. Angiotensin II as a pro-inflammatory
mediator. Curr Opin Investig Drugs. 2002; 3:569-77. [0192] 28.
Miyazaki M, et al. Angiotensin II type I receptor antagonist,
TCV-116, prevents neointima formation in injured arteries in the
dog. Jpn J. Pharmacol. 1999; 79:455-60. [0193] 29. Sasaki K, et al.
Evidence for the importance of angiotensin II type 1 receptor in
ischemia-induced angiogenesis. J Clin Invest. 2002; 109:603-11.
[0194] 30. Silvestre J S, et al. Antiangiogenic effect of
angiotensin II type 2 receptor in ischemia-induced angiogenesis in
mice hindlimb. Circ Res. 2002; 90:1072-9. [0195] 31. Tarrarat R, et
al. Angiotensin II angiogenic effect in vivo involves vascular
endothelial growth factor- and inflammation-related pathways. Lab
Invest. 2002; 82:747-56. [0196] 32. Horiuchi M, et al. Fluvastatin
enhances the inhibitory effects of a selective angiotensin II type
1 receptor blocker, valsartan, on vascular neointimal formation.
Circulation. 2003; 107:106-12.
[0197] Methods claimed in this invention, in part, applies to
natural or synthetic PPAR ligands or activators, described in
detail in the following issued, allowed, pending or provisional
patent applications: [0198] 33. U.S. patent Ser. No. 09/520,208
1,2-Dithiolane Derivatives, pending [0199] 34. U.S. patent Ser. No.
09/684,738 Novel Dithiolane Derivatives [0200] 35. U.S. Pat. No.
6,103,742 Pharmaceutical composition [0201] 36. U.S. Pat. No.
6,100,403 Production of benzaldehyde compounds [0202] 37. U.S. Pat.
No. 6,087,385 Flavonoid derivatives [0203] 38. U.S. Pat. No.
6,087,384 Apoptosis inhibitor [0204] 39. U.S. Pat. No. 6,028,088
Flavonoid derivatives [0205] 40. U.S. Pat. No. RE36,575 Pyridine
and thiazolidinedione derivatives [0206] 41. U.S. Pat. No.
6,022,897 Selective modulators of PPAR( and methods . . . [0207]
42. U.S. Pat. No. 6,011,036 Heterocyclic compounds having
antidiabetic . . . [0208] 43. U.S. Pat. No. 6,011,031
Azolidinediones useful for the treatment of diabetes . . . [0209]
44. U.S. Pat. No. 6,008,237 Arylthiazolidinedione derivatives
[0210] 45. U.S. Pat. No. 5,990,139 Thiazolidinedione derivatives or
salts thereof and . . . [0211] 46. U.S. Pat. No. 5,985,884
Heterocyclic compounds, process for their preparation . . . [0212]
47. U.S. Pat. No. 5,977,365 Heterocyclic compound having
anti-diabetic activity [0213] 48. U.S. Pat. No. 5,972; 970
Oxazolidinedione derivatives, their production and use [0214] 49.
U.S. Pat. No. 5,972,959 Oxime derivatives, their preparation and
therapeutic use [0215] 50. U.S. Pat. No. 5,965,589
Thiazolidinedione derivatives, their production and use [0216] 51.
U.S. Pat. No. 5,962,470 Heterocyclic compounds having anti-diabetic
activity . . . [0217] 52. U.S. Pat. No. 5,952,509 Production of
benzaldehyde compounds [0218] 53. U.S. Pat. No. 5,965,584
Pharmaceutical composition [0219] 54. U.S. Pat. No. 5,952,356
Pharmaceutical composition [0220] 55. U.S. Pat. No. 5,939,442
Modulations of PPAR(, and methods for the use thereof [0221] 56.
U.S. Pat. No. 5,932,601 Oxazolidinedione derivatives, their
production and use [0222] 57. U.S. Pat. No. 5,925,656 Compounds
having antidiabetic, hypolipidemic . . . [0223] 58. U.S. Pat. No.
5,919,782 Heterocyclic compounds having antidiabetic . . . [0224]
59. U.S. Pat. No. 5,910,592 Substituted thiazolidinedione
derivatives [0225] 60. U.S. Pat. No. 5,902,726 Activators of the
nuclear orphan receptor PPAR( [0226] 61. U.S. Pat. No. 5,889,032
Heterocyclic compounds having antidiabetic . . . [0227] 62. U.S.
Pat. No. 5,889,025 Antidiabetic compounds having hypolipidaemic.
[0228] 63. U.S. Pat. No. 5,886,014 Benzimidazole derivatives, their
preparation . . . [0229] 64. U.S. Pat. No. 5,885,997 Heterocyclic
compounds, process for their preparation . . . [0230] 65. U.S. Pat.
No. 5,869,495 Heterocyclic compounds as pharmaceutical [0231] 66.
U.S. Pat. No. 5,859,051 Antidiabetic agents [0232] 67. U.S. Pat.
No. 5,847,008 Method of treating diabetes and related disease
states [0233] 68. U.S. Pat. No. 5,843,970 Thiazolidine derivatives
for the treatment of hypertension [0234] 69. U.S. Pat. No.
5,834,501 Heterocyclic compounds having anti-diabetic activity . .
. [0235] 70. U.S. Pat. No. 5,827,865 Heterocyclic compounds as
pharmaceutical [0236] 71. U.S. Pat. No. 5,824,694 Thiazolidine
derivatives for the treatment of psoriasis [0237] 72. U.S. Pat. No.
5,811,439 Thiazolidinedione derivatives, method for preparing . . .
[0238] 73. U.S. Pat. No. 5,801,173 Heterocyclic compounds having
antidiabetic . . . [0239] 74. U.S. Pat. No. 5,741,803 Substituted
thiazolidinedionle derivatives [0240] 75. U.S. Pat. No. 5,693,651
Quinoline derivatives [0241] 76. U.S. Pat. No. 5,506,245
Thiazolidinedione compounds [0242] 77. U.S. Pat. No. 6,150,371
Method for preventing and for treating autoimmune . . . [0243] 78.
WO 01/12612 Benzoic acid derivatives for the treatment of diabetes
. . . [0244] 79. WO 98/57941 New thiazolidinedione,
oxazolidinedione . . . [0245] 80. WO 01/00603 Thiazole and oxazole
derivatives . . . [0246] 81. WO 97/25042 Use of an antagonist of
PPAR-alpha and PPAR-gamma . . . [0247] 82. WO 98/05331 Prevention
or treatment of type 2 diabetes or cardiovascular . . . [0248] 83.
WO 97/28137 Heterocyclic derivatives as antidiabetic and
antiobesity . . . [0249] 84. WO 00/27832 PPAR.gamma. ligands [0250]
85. WO 01/21602 Oxa- and thiazole derivatives. [0251] 86. WO
01/34094 Novel compounds to treat diabetes . . . [0252] 87. WO
99/62870 New 3-aryl-2-hydroxypropionic acid . . . [0253] 88. WO
99/62871 New 3-aryl-2-hydroxypropionic acid . . . [0254] 89. WO
99/62872 New 3-aryl-2-hydroxypropionic acid . . . [0255] 90. U.S.
Pat. No. 5,864,043 Benzimidazoles, medicaments . . . [0256] 91.
U.S. Pat. No. 5,684,029 Benzimidazoles, pharmaceutical compositions
. . . [0257] 92. U.S. Pat. No. 5,614,519 (1-(2, 3 or
4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls
useful as angiotensin-II antagonists [0258] 93. U.S. Pat. No.
5,602,127 (Alkanesultam-1-yl)-benzimidazol-1-yl)-1
yl)-methyl-biphenyls useful as angiotensin-II antagonists [0259]
94. U.S. Pat. No. 5,594,003
Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls
useful as angiotensin-II antagonists [0260] 95. U.S. Pat. No.
5,591,762 Benzimidazoles useful as angiotensin-11 antagonists
[0261] 96. U.S. Pat. No. 5,587,393 Benzimidazoles, pharmaceutical
compositions . . . [0262] 97. U.S. Pat. No. 5,565,469
Benzimidazoles and pharmaceutical compositions [0263] 98. U.S. Pat.
No. 5,541,229 Benzimidazoles and medicaments [0264] 99. U.S. Pat.
No. 6,355,808 Benzimidazole compounds, their production and use
[0265] 100. U.S. Pat. No. 6,232,334 Benzimidazole derivatives,
their production and use [0266] 101. U.S. Pat. No. 6,004,989
Benzimidazole derivatives, their production and use [0267] 102.
U.S. Pat. No. 5,962,491 Benzimidazole derivatives and use thereof
[0268] 103. U.S. Pat. No. 5,883,111 Heterocyclic compounds and
their use as angiotensin . . . [0269] 104. U.S. Pat. No. 5,736,555
Heterocyclic compounds and their use as angiotensin . . . [0270]
105. U.S. Pat. No. 5,705,517 Benzimidazole derivatives and use
thereof [0271] 106. U.S. Pat. No. 5,703,110 Benzimidazole
derivatives, their production and use [0272] 107. U.S. Pat. No.
5,583,141 Heterocyclic compounds and their use as angiotensin . . .
[0273] 108. U.S. Pat. No. 5,500,427 Cyclic compounds and their use
[0274] 109. U.S. Pat. No. 5,496,835 Heterocyclic compounds having
angiotensin II . . . [0275] 110. U.S. Pat. No. 6,160,000
Antidiabetic agents based on aryl and heteroarylacetic acids [0276]
111. U.S. Pat. No. 6,113,907 Pharmaceutical grade St. John's Wort
[0277] 112. U.S. Pat. No. 6,090,839 Antidiabetic agents [0278] 113.
U.S. Pat. No. 6,090,836 Benzisoxazole-derived antidiabetic
compounds [0279] 114. U.S. Pat. No. 6,020,382 Method of treating
diabetes and related disease states [0280] 115. U.S. Pat. No.
5,958,942 Tricyclic nitrogen ring compounds, their production and
use [0281] 116. U.S. Pat. No. 5,859,051 Antidiabetic agents [0282]
117. U.S. Pat. No. 5,847,008 Method of treating diabetes and
related disease states [0283] 118. U.S. Pat. No. 5,843,172 Porous
medicated stent [0284] 119. U.S. Pat. No. 5,663,187 Treatment of
atherosclerosis with angiotensin II receptor blocking imidazoles
[0285] 120. U.S. Pat. No. 5,663,186 Treatment of atherosclerosis
with angiotensin II receptor blocking imidazoles [0286] 121. U.S.
Pat. No. 6,160,000 Antidiabetic agents based on aryl and
heteroarylacetic acids\ [0287] 122. U.S. Pat. No. 6,479,524
Substituted aryl and heteroaryl derivatives . . . [0288] 123. U.S.
Pat. No. 6,476,023 Aromatic heterocyclic compounds as
anti-inflammatory agents [0289] 124. U.S. Pat. No. 6,469,039
Disubstituted bicyclic heterocycles . . . [0290] 125. U.S. Pat. No.
6,451,832 Benzimidazoles with antithrombotic activity [0291] 126.
U.S. Pat. No. 6,414,008 Disubstituted bicyclic heterocycles . . .
[0292] 127. U.S. Pat. No. 6,372,773 Aromatic heterocyclic compounds
as antiinflammatory agents [0293] 128. U.S. Pat. No. 6,358,945
Compounds useful as anti-inflammatory agents [0294] 129. U.S. Pat.
No. 6,333,325 Method of treating cytokine mediated diseases or
conditions [0295] 130. U.S. Pat. No. 6,329,415 Aromatic
heterocyclic compounds as antiinflammatory agents [0296] 131. U.S.
Pat. No. 6,150,371 Method for preventing and for treating
autoimmune disease [0297] 132. U.S. Pat. No. 6,117,893 Heterocyclic
compounds having anti-diabetic activity . . . [0298] 133. U.S. Pat.
No. 6,414,002 Substituted acid derivatives useful as antidiabetic
and antiobesity agents . . . [0299] 134. U.S. Pat. No. 6,432,996
Pharmaceutical composition [0300] 135. U.S. Pat. No. 6,432,993
Substituted fused heterocyclic compound (rivoglitazone) . . .
[0301] 136. U.S. Pat. No. 6,486,188 Method of treatment for
cardiovascular complications [0302] 137. U.S. Pat. No. 6,420,405
Pharmaceutical composition for angiotensin II-mediated . . . [0303]
138. U.S. Pat. No. 6,468,996 Substituted hetero-polycyclic
compounds as PPAR.alpha./PPAR.gamma.. [0304] 139. U.S. Pat. No.
6,432,996 Pharmaceutical composition [0305] 140. U.S. Pat. No.
6,355,808 Benzimidazole compounds, their production and use [0306]
141. U.S. Pat. No. 6,348,481 Pharmaceutical composition for
angiotensin II-mediated [0307] 142. U.S. Pat. No. 6,232,334
Benzimidazole derivatives, their production and use [0308] 143.
U.S. Pat. No. 6,228,874 Pharmaceutical composition for angiotensin
II-mediated . . . [0309] 144. U.S. Pat. No. 6,100,252 Heterocyclic
compounds and their use as angiotensin antagonists [0310] 145. U.S.
Pat. No. 5,958,961 Pharmaceutical composition for angiotensin
II-mediated diseases [0311] 146. U.S. Pat. No. 5,639,773 Ocular
hypotensive agent [0312] 147. U.S. Pat. No. 6,355,808 Benzimidazole
compounds, their production and use [0313] 148. U.S. Pat. No.
6,232,334 Benzimidazole derivatives, their production and use
[0314] 149. U.S. Pat. No. 5,463,073 Thienoimidazole derivatives,
their production and use [0315] 150. U.S. Pat. No. 5,401,764
Benzimidazole derivative compositions and medical use thereof
[0316] 151. U.S. Pat. No. 5,389,641 Fused heterocyclic compounds,
having angiotensin II antagonistic activity [0317] 152. U.S. Pat.
No. 5,354,766 Compound and salts thereof which antagonize
angiotensin II [0318] 153. U.S. Pat. No. 5,328,919
Pivaloyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]
benzimidazole-7-carboxylate or a pharmaceutically acceptable salt
thereof . . . [0319] 154. U.S. Pat. No. 5,284,661 Fused thiophene
derivatives, their production and use [0320] 155. U.S. Pat. No.
5,250,554 Benzimidazole derivatives useful as angiotensin II
inhibitors [0321] 156. U.S. Pat. No. 5,243,054 Compound which is
angiotensin II antagonist [0322] 157. U.S. Pat. No. 5,196,444
1-(cyclohexyloxycarbonyloxy)ethyl
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca-
rboxylate . . . [0323] 158. U.S. Pat. No. 5,162,326 Pyrimidinedione
derivatives, their production and use [0324] 159. U.S. Pat. No.
5,128,356 Benzimidazole derivatives and their use [0325] 160. U.S.
Pat. No. 6,200,995 PPAR.gamma. modulators (Tularik) [0326] 161.
U.S. Prov. Pat. No. 60/283,774 Optimized ligands for PPARs [0327]
162. U.S. Prov. Pat. No. 60/189,514 Novel Antioxidants [0328] 163.
U.S. Prov. Pat. No. 60/402,425 Identification and uses of novel
PPAR ligands that do not cause fluid retention
[0329] The above-named patents contain the description of compounds
that can be utilized in the practice of this invention.
Consequently said compounds are covered according to the claims of
this invention.
[0330] All publications, patents and patent publications mentioned
in this specification are herein incorporated by reference into the
specification in their entirety for all purposes.
[0331] Although the invention has been described with reference to
preferred embodiments and examples thereof, the scope of the
present invention is not limited only to those described
embodiments. As will be apparent to persons skilled in the art,
modifications and adaptations to the above-described invention can
be made without departing from the spirit and scope of the
invention, which is defined and circumscribed by the appended
claims.
[0332] The foregoing is offered primarily for purposes of
illustration. It will be readily apparent to those of ordinary
skill in the art that the operating conditions, materials,
procedural steps and other parameters of the invention described
herein may be further modified or substituted in various ways
without departing from the spirit and scope of the invention. For
example, the invention has been described with human patients as
the usual recipient, but veterinary use is also contemplated. Thus,
the preceding description of the invention should not be viewed as
limiting but as merely exemplary.
* * * * *