Inhibitors of adp-ribosyl transferases, cyclases, and hydrolases

Abstract

The present invention provides compounds having the formula: (I); Also provided are pro-drug compounds of the formula: (II); The invention also provides pharmaceutical compositions containing the above compounds, methods of using the above compounds as pharmaceuticals, and processes for preparing the above compounds. Methods for inhibiting an ADP-ribosyl transferase, ADP-ribosyl cyclase, ADP-ribosyl hydrolase, or NAD-dependent deacetylase enzyme using the above compounds, and methods for treating a disease or condition associated with an ADP-ribosyl transferase, ADP-‘ribosyl cyclase, ADP-ribosyl hydrolase, or NAD-dependent deacetylase enzyme in a subject using the above compounds are also provided.

1 - 26 . (canceled)  
   
   
       27 . A compound represented by the formula:  
     
       
         
         
             
             
         
       
     
     wherein A is a nitrogen-, oxygen-, or sulfur-linked aryl, alkyl, cyclic, or heterocyclic group; B is hydrogen, or a halogen, amino, or thiol group; C is hydrogen, or a halogen, amino, or thiol group; D is the ester —OOCR where R is an alkyl or an aryl, a primary alcohol, a hydrogen, or an oxygen, nitrogen, carbon, or sulfur linked to phosphate, a phosphoryl group, a pyrophosphoryl group, or adenosine monophosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted phosphodiester bridge, or to adenosine diphosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted pyrophosphodiester bridge; and E is OH or the ester —OOCR where R is an alkyl or an aryl, 
 provided at least one of D or E is the ester —OOCR where R is an alkyl or an aryl.  
 
   
   
       28 . The compound of  claim 27 , wherein the compound, when treated with an esterase, inhibits at least one enzyme selected from the group consisting of an ADP-ribosyl transferase, an ADP-ribosyl cyclase, an ADP-ribosyl hydrolase, and an NAD-dependent deacetylase enzyme.  
   
   
       29 . The compound of  claim 28 , wherein the enzyme is a CD38.  
   
   
       30 . The compound of  claim 27 , wherein A is further substituted with an electron contributing moiety  
   
   
       31 . The compound of  claim 30 , wherein the electron contributing moiety is selected from the group consisting of methyl, ethyl, O-methyl, amino, NMe 2 , hydroxyl, CMe 3 , aryl and C3-C10 alkyl.  
   
   
       32 - 34 . (canceled)  
   
   
       35 . The compound of  claim 27 , wherein A is capable of base exchange with nicotinamide in the presence of a CD38.  
   
   
       36 . The compound of  claim 27 , wherein both D and E are the ester —OOCR where R is an alkyl or an aryl.  
   
   
       37 . The compound of  claim 27 , wherein A is an N-linked aryl or heterocyclic group.  
   
   
       38 . The compound of  claim 27 , wherein A is a substituted nicotinamide, pyrazolo, or imidazolo group.  
   
   
       39 . The compound of  claim 27 , which is a methyl-nicotinamide-2′-deoxyriboside ester.  
   
   
       40 . The compound of  claim 27 , which is a 
 5-methyl-nicotinamide-2′-deoxyriboside ester or a    4-methyl-nicotinamide-2′-deoxyriboside ester.    
   
   
       41 . The compound of  claim 27 , which is an ester of 
 β-1′-5-methyl-nicotinamide-2′-deoxyribose,    β-D-1′-5-methyl-nicotinamide-2′-deoxyribofuranoside,    β-1′-4-methyl-nicotinamide-2′-deoxyribose,    β-D-1′-4-methyl-nicotinamide-2′-deoxyribofuranoside,    β-1′-4,5-dimethyl-nicotinamide-2′-deoxyribose or    β-D-1′-4,5-dimethyl-nicotinamide-2′-deoxyribofuranoside.    
   
   
       42 . The compound of  claim 27 , which is an ester of β-1′-5-methyl-nicotinamide-2′-deoxyribose.  
   
   
       43 - 44 . (canceled)  
   
   
       45 . The compound of  claim 27 , wherein both B and C are hydrogen, or either B or C is a halogen, amino, or thiol group and the other of B or C is hydrogen.  
   
   
       46 . The compound of  claim 27 , wherein D is a primary alcohol or hydrogen.  
   
   
       47 . A pharmaceutical composition comprising the compound of  claim 28  and a pharmaceutically-acceptable carrier.  
   
   
       48 . A method for inhibiting an ADP-ribosyl transferase, ADP-ribosyl cyclase, ADP-ribosyl hydrolase, or NAD-dependent deacetylase enzyme, comprising contacting the enzyme with an esterase and an amount of the compound of  claim 28  effective to inhibit the enzyme.  
   
   
       49 . The method of  claim 48 , wherein the enzyme is a CD38.  
   
   
       50 . The method of  claim 48 , wherein the enzyme is in a viable mammalian cell.  
   
   
       51 . The method of  claim 50 , wherein the cell is in a mammal.  
   
   
       52 - 53 . (canceled)