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.

1 . A method for treating or limiting the rate of progression of polycystic kidney disease, comprising orally administering to a mammal in need thereof a therapeutically effective amount of a compound sufficient to (a) at least partially activate peroxisome proliferator activated receptor-gamma (PPAR-gamma) and (b) at least partially inhibit, antagonize or block an activity of angiotensin II type 1 receptors, wherein the therapeutically effective amount is about 20 mg to about 1000 mg. 
     
     
         2 . The method of  claim 1  wherein the compound is administered in a pharmaceutically acceptable form. 
     
     
         3 . The method of  claim 1  wherein the compound is telmisartan or an analog thereof. 
     
     
         4 . The method of  claim 1  wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease and the compound is telmisartan. 
     
     
         5 . The method of  claim 1  wherein the compound is telmisartan and the effective daily orally administered dose of telmisartan is about 80 mg. 
     
     
         6 . The method of  claim 1  wherein the compound is telmisartan and the effective daily orally administered dose of telmisartan is about 160 mg. 
     
     
         7 . The method of  claim 1  wherein the compound is telmisartan and the telmisartan is administered in combination with ramipril. 
     
     
         8 . The method of  claim 1  wherein the compound is telmisartan and the telmisartan is administered in combination with lisinopril. 
     
     
         9 . The method of  claim 7  wherein 1 part by weight of telmisartan is administered in combination with 0.01 to 100 parts by weight of ramipril. 
     
     
         10 . The method of  claim 8  wherein 1 part by weight of telmisartan is administered in combination with 0.01 to 100 parts by weight of lisinopril. 
     
     
         11 . The method of  claim 9  wherein the telmisartan and the ramipril are administered as separate compositions. 
     
     
         12 . The method of  claim 9  wherein the telmisartan and the ramipril are administered as a single composition. 
     
     
         13 - 17 . (canceled) 
     
     
         18 . An article of manufacture comprising a composition comprising 1 part by weight of telmisartan and a composition comprising 0.01 to 100 parts by weight of ramipril. 
     
     
         19 . The article of manufacture of  claim 18  wherein the telmisartan and the ramipril are in separate compositions. 
     
     
         20 . The article of manufacture of  claim 18  wherein the telmisartan and the ramipril are in a single composition. 
     
     
         21 - 23 . (canceled) 
     
     
         24 . A method for treating or limiting the rate of progression of polycystic kidney disease, comprising orally administering to an adult human in need thereof a therapeutically effective amount of telmisartan sufficient to (a) at least partially activate peroxisome proliferator activated receptor-gamma (PPAR-gamma) and (b) at least partially inhibit, antagonize or block an activity of angiotensin II type 1 receptors, wherein the therapeutically effective amount is about 20 mg to about 1,000 mg. 
     
     
         25 . The method of  claim 24 , wherein the therapeutically effective amount of telmisartan is about 80 mg or about 160 mg, and wherein the therapeutically effective amount of telmisartan is optionally administered in combination with ramipril or lisinopril such that 1 part by weight of the telmisartan is optionally administered in combination with 0.01 to 100 parts by weight of ramipril or 0.01 to 100 parts by weight of lisinopril.