Class of HDAC Inhibitors Expands the Renal Progenitor Cells Population and Improves the Rate of Recovery from Acute Kidney Injury

Abstract

Compounds and compositions are provided that inhibit histone deacylase activity and which expand renal progenitor cell populations and improve kidney function in a damaged kidney. Methods of use of the compounds and compositions are provided.

What is claimed is: 
     
         1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R is S, S(O), S(O) 2  or NH; 
         R1 is —NHR4 where R4 is OH, aminophenyl, hydroxyphenyl, C 1-4  alkyl hydroxyphenyl or phenyl hydroxyphenyl, or —OR5 where R5 is H or C 1-4  alkyl; 
       
       
         
           
           
               
               
           
         
         R2 is phenyl; substituted phenyl, where R5 is halo; methyl; C 1-4  alkyl; methoxy; C 1-4  alkoxy; naphthyl; 1H-1,3-benzodiazol-2-yl; 1,3-benzothiazol-2-yl; pyrimidinyl; 1-methyl-1H-1,3benzodiazol-2-yl; pyridyl; methoxyphenyl; or methylthiophenyl; and 
         R3 is from 0 to 5 methylene groups ((—CH 2 —) 0-5 ) or 0 or 1 phenylene wherein at least one methylene or phenylene is present, 
         or a pharmaceutically acceptable salt thereof, other than 4-(phenylthio)butanoic acid. 
       
     
     
         2 . The compound of  claim 1 , wherein R is S. 
     
     
         3 . The compound of  claim 2 , wherein R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —. 
     
     
         4 . The compound of  claim 2 , wherein R2 is phenyl, 4-fluorophenyl, 4-methoxyphenyl, or 4-methylphenyl. 
     
     
         5 . The compound of  claim 2 , wherein R3 is —CH 2 —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 — and R2 is phenyl, 4-fluorophenyl, 4-methoxyphenyl or 4-methylphenyl. 
     
     
         6 . The compound of  claim 2 , wherein R1 is —NH—OH, —NH-2-aminophenyl, -NH-2-hydroxyphenyl, or —O—CH 3 . 
     
     
         7 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . A composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein, 
         R is S, S(O), S(O) 2 , or NH; 
         R1 is —NHR4, where R4 is OH, aminophenyl, hydroxyphenyl, C 1-4  alkyl hydroxyphenyl, phenyl hydroxyphenyl, or —OR5 where R5 is H or C 1-4  alkyl; 
       
       
         
           
           
               
               
           
         
         R2 is phenyl; substituted phenyl, where R5 is halo; methyl, C 1-4  alkyl; methoxy; C 1-4  alkoxy; naphthyl; 1H-1,3-benzodiazol-2-yl; 1,3-benzothiazol-2-yl; pyrimidinyl; 1-methyl-1H-1,3benzodiazol-2-yl; pyridyl; methoxyphenyl; or methylthiophenyl; and 
         R3 is from 0 to 5 methylene groups ((—CH 2 -) 0-5 ) or 0 or 1 phenylene wherein at least one methylene or phenylene is present, 
         or a pharmaceutically acceptable salt thereof, in an amount effective to increase renal progenitor cell production in a kidney of a patient, and a pharmaceutically-acceptable excipient. 
       
     
     
         13 . The composition of  claim 12 , wherein R is S. 
     
     
         14 . The composition of  claim 13 , wherein R3 is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —. 
     
     
         15 . The composition of  claim 13 , wherein R2 is phenyl, 4-fluorophenyl, 4-methoxyphenyl, or 4-methylphenyl. 
     
     
         16 . The composition of  claim 13 , wherein R3 is —CH 2 —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, and R2 is phenyl, 4-fluorophenyl, 4-methoxyphenyl, or 4-methylphenyl. 
     
     
         17 . The composition of  claim 13 , wherein R1 is —NH—OH, —NH-2-aminophenyl, NH-2-hydroxyphenyl, or —O—CH 3 . 
     
     
         18 . The composition of  claim 12 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any of the preceding. 
       
     
     
         19 . The composition of  claim 12 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . The composition of  claim 12 , comprising a cyclodextrin complexed with the compound.