Inhibition of fatty acid synthesis by iodo-nitrobenzamide compounds and methods of treatment thereof

Abstract

The present invention relates to a method of treating a fatty acid synthesis related disease comprising administering to a patient in need thereof an effective amount of a PARP inhibitor or metabolite thereof to inhibit fatty acid synthesis, wherein the fatty acid synthesis related disease is obesity, diabetes, or cardiovascular disease. The present invention also relates to a method of treating a cancer in a subject comprising: (i) identifying a level of fatty acid in a sample from the subject, and (ii) administering an effective amount of a PARP inhibitor or metabolite thereof to inhibit fatty acid synthesis in the subject, wherein the administration is based on the level of fatty acid, thereby treating the cancer in the subject. The present invention further relates to a method of treating Her-2 related cancers by administering to a patient in need thereof an effective amount of a PARP inhibitor or metabolite thereof to inhibit fatty acid synthesis.

1 . A method of treating a fatty acid synthesis related disease comprising administering to a patient in need thereof an effective amount of a compound of formula Ia or metabolite thereof or a pharmaceutically acceptable salt thereof to inhibit a fatty acid synthesis, wherein said fatty acid synthesis related disease is obesity, and wherein the compound of formula Ia is a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , and R 5  are, independently selected from the group consisting of hydrogen, hydroxy, amino, nitro, iodo, bromo, fluoro, chloro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl, and phenyl, wherein at least two of the five R 1 , R 2 , R 3 , R 4 , and R 5  substituents are always hydrogen, at least one of the five substituents is always nitro, and at least one substituent positioned adjacent to a nitro is always iodo, or a metabolite thereof or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein said fatty acid synthesis inhibited is synthesis of a medium chain fatty acid or a long chain fatty acid. 
     
     
         3 . The method of  claim 1 , wherein said inhibition of said fatty acid synthesis comprises inhibiting at least one enzyme of a glucose pathway. 
     
     
         4 . The method of  claim 1 , wherein said inhibition of said fatty acid synthesis comprises inhibiting at least one enzyme of a fatty acid biosynthetic pathway. 
     
     
         5 . The method of  claim 1 , wherein said inhibition of said fatty acid synthesis comprises inhibiting at least one enzyme selected from the group consisting of acetyl Co-A, malonyl Co-A, acetyl Co-A carboxylase, and fatty acid synthase. 
     
     
         6 . The method of  claim 1 , wherein said inhibition of said fatty acid synthesis comprises inhibiting at least one enzyme of a fatty acid synthase. 
     
     
         7 . The method of  claim 6 , wherein said fatty acid synthase comprises acyl carrier protein, acetyl transferase, malonyl transferase, 3-keto-acyl-ACP synthase, 3-ketoacyl-ACP reductase, 3-hydroxy-acyl-ACP dehydratase, and enoyl-ACP reductase. 
     
     
         8 . The method of  claim 1 , wherein said inhibition of said fatty acid synthesis comprises inhibiting synthesis of an acetyl-CoA from a glucose. 
     
     
         9 . The method of  claim 1 , wherein said inhibition of said fatty acid synthesis comprises inhibiting said fatty acid synthesis from an acetyl-CoA. 
     
     
         10 . The method of  claim 1 , wherein said inhibition is determined by analyzing a metabolite or a molecular flux of a glucose pathway or a fatty acid biosynthetic pathway. 
     
     
         11 . The method of  claim 10 , wherein said metabolite of said glucose pathway or said fatty acid biosynthetic pathway is selected from the group consisting of glucose, glycogen, lactate, CO 2 , fatty acid, acetyl Co-A, RNA ribose and DNA deoxyribose. 
     
     
         12 . The method of  claim 11 , wherein said metabolite of said glucose pathway or said fatty acid biosynthetic pathway is chemically derivatized for said analysis. 
     
     
         13 . The method of  claim 12 , wherein said analysis comprises mass spectrometry. 
     
     
         14 . The method of  claim 13 , wherein said mass spectrometry is mass isotopomer distribution analysis. 
     
     
         15 - 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein said compound of Formula Ia is a compound of formula III, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 1 , wherein said treatment is selected from the group consisting of oral administration, transmucosal administration, buccal administration, nasal administration, inhalation, parental administration, intravenous, subcutaneous, intramuscular, sublingual, transdermal administration, and rectal administration. 
     
     
         19 - 96 . (canceled) 
     
     
         97 . The method of  claim 1 , wherein the metabolite of the compound of formula (Ia) is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt thereof, and 
         a compound of formula MS213 
       
       
         
           
           
               
               
           
         
       
       wherein R 6  is selected from the group consisting of hydrogen, alkyl (C 1 -C 8 ), alkoxy (C 1 -C 8 ), isoquinolinones, indoles, thiazole, oxazole, oxadiazole, thiophene, or phenyl.