Methods of Treating Fatty Liver Disease

Abstract

The disclosure provides methods for treating fatty liver disease and associated conditions by inhibiting the synthesis of glucosphingolipids, as exemplified by the use of glucosylceramide synthase substrate analogs.

1 - 44 . (canceled) 
     
     
         45 . A method of treating a fatty liver disease selected from alcoholic fatty liver disease, nonalcoholic fatty liver disease (NAFLD), acute fatty liver of pregnancy, macrovesicular steatosis or microvesicular steatosis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 1  is chosen from substituted and unsubstituted aryl; R 2  is chosen from substituted and unsubstituted alkyl; and R 3  is chosen from substituted and unsubstituted tertiary cyclic amino. 
     
     
         46 . The method of  claim 45 , wherein R 1  is chosen from substituted and unsubstituted phenyl. 
     
     
         47 . The method of  claim 46 , wherein R 1  is 1,4-benzodioxan-6-yl. 
     
     
         48 . The method of  claim 45 , wherein R 2  is chosen from substituted and unsubstituted C 7 -C 18  alkyl. 
     
     
         49 . The method of  claim 48 , wherein R 2  is chosen from substituted and unsubstituted C 7  alkyl. 
     
     
         50 . The method of  claim 48 , wherein R 2  is chosen from substituted and unsubstituted C 8  alkyl. 
     
     
         51 . The method of  claim 45 , wherein R 3  is pyrrolidino. 
     
     
         52 . The method of  claim 51 , wherein R 2  is C 7  alkyl. 
     
     
         53 . The method of  claim 51 , wherein R 2  is C 8  alkyl. 
     
     
         54 . The method of  claim 45 , wherein the compound of Formula I is 1-(1,4-benzodioxan-6-yl)-2-nonanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method of  claim 54 , wherein the compound of Formula I is 1(R)-(1,4-benzodioxan-6-yl)-2(R)-nonanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 45 , wherein the compound of Formula I is 1-(1,4-benzodioxan-6-yl)-2-octanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof. 
     
     
         57 . The method of  claim 56 , wherein the compound of Formula I is 1(R)-(1,4-benzodioxan-6-yl)-2(R)-octanoylamino-3-pyrrolidino-1-propanol, or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The method of  claim 45 , wherein the compound of Formula I is in the form of a pharmaceutically acceptable salt. 
     
     
         59 . The method of  claim 58 , wherein the pharmaceutically acceptable salt is tartrate. 
     
     
         60 . The method of  claim 45 , further comprising administering to the subject at least one compound selected from the group consisting of an α-glucosidase inhibitor, a biguanide, insulin, a meglitinide, a sulfonylurea, a thiazolidinedione, an antioxidant, a lipid-lowering agent, a weight-loss agent, a cytoprotective agent, an alpha-2 adrenergic agonist, an anticonvulsant, a barbiturate, a benzodiazepine, a beta-adrenergic blocker, disulfiram, an opioid antagonist, a phenothiazine, and a serotonin reuptake inhibitor. 
     
     
         61 . The method of  claim 45 , wherein the fatty liver disease is alcoholic fatty liver disease. 
     
     
         62 . The method of  claim 45 , wherein the fatty liver disease is nonalcoholic fatty liver disease (NAFLD). 
     
     
         63 . The method of  claim 45 , wherein the fatty liver disease is acute fatty liver of pregnancy. 
     
     
         64 . The method of  claim 45 , wherein the fatty liver disease is macrovesicular steatosis or microvesicular steatosis.