Treatment of fibrosis using fxr ligands

Abstract

The present invention relates to a method for inhibiting fibrosis that occurs in an organ where the farnesoid X receptor (FXR) is expressed. This method involves the step of administering a high potency, activating ligand of FXR in an effective amount to a patient who is suffering from a cholestatic condition. The invention also provides pharmaceutical compositions containing an effective amount of an FXR ligand and kits for dispensing the pharmaceutical compositions.

1 . A method for inhibiting fibrosis in a subject not suffering from a cholestatic condition, the method comprising the step of administering to the subject an effective amount of a ligand specific for the farnesoid X receptor (FXR), wherein the fibrosis to be inhibited occurs in an organ where FXR is expressed, with the proviso that the ligand is not chenodeoxyxholic acid (CDCA) or ursodeoxycholic acid (UDCA). 
     
     
         2 . A method for inhibiting fibrosis in a subject not suffering from a cholestatic condition, the method comprising the step of administering to the subject an effective amount of a ligand specific for the farnesoid X receptor (FXR), wherein the fibrosis to be inhibited occurs in an organ where FXR is expressed, with wherein the ligand has an EC 50  no greater than 5 μM in a cell-free FXR assay or in a cell-based FXR transactivation assay. 
     
     
         3 . The method of  claim 2 , wherein the ligand has an EC 50  no greater than 1 μM. 
     
     
         4 . The method of  claim 1 , wherein the cholestatic condition is defined as having abnormally elevated serum levels of alkaline phosphatase, γ-glutamyl transpeptidase (GGT), and 5′ nucleotidase. 
     
     
         5 . The method of  claim 4 , wherein the cholestatic condition is further defined as presenting with at least one clinical symptom. 
     
     
         6 . The method of  claim 5 , wherein the symptom is itching (pruritus). 
     
     
         7 . The method of  claim 1 , wherein the fibrosis is selected from the group consisting of liver fibrosis, kidney fibrosis, and intestinal fibrosis. 
     
     
         8 . The method of  claim 1 , wherein the cholestatic condition is selected from the group consisting of primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced cholestasis, hereditary cholestasis, and intrahepatic cholestasis of pregnancy. 
     
     
         9 . The method of  claim 1 , wherein the subject is not suffering from a cholestatic condition associated with a disease or condition selected from the group consisting of primary liver and biliary cancer, metastatic cancer, sepsis, chronic total parenteral nutrition, cystic fibrosis, and granulomatous liver disease. 
     
     
         10 . The method of  claim 1 , wherein the ligand is selected from the group consisting of 6ECDCA, tauro-6ECDCA, 6EUDCA, GW4064, 6α-MeCDCA, 6α-PrCDCA, fexaramine, and guggulsterone. 
     
     
         11 . The method of  claim 1 , wherein the subject has liver fibrosis associated with a disease selected from the group consisting of hepatitis B; hepatitis C; parasitic liver diseases; post-transplant bacterial, viral and fungal infections; alcoholic liver disease (ALD); non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); liver diseases induced by methotrexate, isoniazid, oxyphenistatin, methyldopa, chlorpromazine, tolbutamide, or amiodarone; autoimmune hepatitis; sarcoidosis; Wilson's disease; hemochromatosis; Gaucher's disease; types III, IV, VI, IX and X glycogen storage diseases; ai-antitrypsin deficiency; Zellweger syndrome; tyrosinemia; fructosemia; galactosemia; vascular derangement associated with Budd-Chiari syndrome, veno-occlusive disease, or portal vein thrombosis; and congenital hepatic fibrosis. 
     
     
         12 . The method of  claim 1 , wherein the subject has intestinal fibrosis associated with a disease selected from the group consisting of Crohn's disease, ulcerative colitis, post-radiation colitis, and microscopic colitis. 
     
     
         13 . The method of  claim 1 , wherein the subject has renal fibrosis associated with a disease selected from the group consisting of diabetic nephropathy, hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease. 
     
     
         14 . A kit for inhibiting fibrosis in a subject not suffering from a cholestatic condition, wherein the fibrosis to be inhibited occurs in an organ where farnesoid X receptor (FXR) is expressed, the kit comprising:
 an effective amount of a ligand specific for FXR, with the proviso that the ligand is not chenodeoxyxholic acid (CDCA) or ursodeoxycholic acid (UDCA); and,   an instructional material teaching the indications, dosage, and schedule of administration of the ligand to the patient.   
     
     
         15 .- 16 . (canceled) 
     
     
         17 . The kit of  claim 14 , wherein the fibrosis is selected from the group consisting of liver fibrosis, kidney fibrosis, and intestinal fibrosis. 
     
     
         18 . The kit of  claim 14 , wherein the ligand is selected from the group consisting of 6ECDCA, tauro-6ECDCA, 6EUDCA, GW4064, 6α-MeCDCA, 6α-PrCDCA, fexaramine, and guggulsterone. 
     
     
         19 . The kit of  claim 14 , wherein the ligand is presented in a pharmaceutical composition suitable for oral or intravenous administration.