C8-substituted purine nucleotide analogs and their use as inhibitors of nucleoside triphosphate diphosphohydrolases

Abstract

Ectonucleoside triphosphate diphosphohydrolases [NTPDases; EC 3.6.1.5] constitute a family of enzymes which are involved in the metabolism of extracellular nucleotides, catalysing the hydrolysis of the gamma and beta phosphate bonds of triphospho- and diphosphonucleosides (whereas 5′nucleotidases [EC 3.1.3.5] catalyse the hydrolysis of alpha phosphate bond of monophosphonucleosides). These extracellular nucleotides interact with endothelial, epithelial and smooth muscle cells, as well as blood cells and lymphoid cells, to influence the different physiological systems of vertebrates. Since these ecto-nucleotidases alter the extracellular concentrations of nucleotides these enzymes modulate their physiological effects, including, for example, platelet aggregation, heart function, control of vascular tone and inflammation reactions, electrolyte secretion and gastrointestinal motility, neurotransmission both in central and peripheral nervous systems, as well as other effects in other physiological systems. This invention provides C8 substituted purine nucleotide analogues, such as ATP analogues, and further provides their use as inhibitors of NTPDases and thereby as tools to modulate the conversion of nucleotides into nucleoside derivatives, and thus modulate the levels of these compounds. Such modulation further provides for the modulation of the activity and function of many processes which are affected by these compounds.

1 . A method for modulating the activity of an NTPDase enzyme comprising exposing the enzyme to a C8 substituted purine nucleotide, wherein the purine nucleotide is substituted at the C8 position with a substituent other than H.  
     
     
         2 . The method of  claim 1 , wherein the purine nucleotide is adenine.  
     
     
         3 . The method of  claim 1 , wherein the substituent is selected from the group consisting of an ether, a thioether and an amine.  
     
     
         4 . The method according to  claim 1 , wherein the activity of the NTPDase enzyme is inhibited.  
     
     
         5 . The method of  claim 3 , wherein the substituent is an ether, and wherein the ether substituent has the structure: 
       —O—X. 
     
     
         6 . The method of  claim 5 , wherein X is an alkyl group.  
     
     
         7 . The method of  claim 6 , wherein X is selected from the group consisting of: 
 (a) C 7 H 13  (cycloheptyl);    (b) (CH 3 ) 3 CCH 2 ; and    (c) CH 3 (CH 2 ) n , wherein 1≦n≦5.    
     
     
         8 . The method of  claim 3 , wherein the substituent is a thioether, and wherein the thioether substituent has the structure: 
       —S—X 
     
     
         9 . The method of  claim 8 , wherein X is an alkyl group.  
     
     
         10 . The method of  claim 9 , wherein X is selected from the group consisting of: 
 (a) C 7 H 13  (cycloheptyl);    (b) (CH 3 ) 3 CCH 2 ; and    (c) CH 3 (CH 2 ) n , wherein 1≦n≦5.    
     
     
         11 . The method of  claim 3 , wherein the substituent is an amine, and wherein the amine substituent has the structure: 
       —NH—X. 
     
     
         12 . The method of  claim 11 , wherein X is an alkyl group.  
     
     
         13 . The method of  claim 12 , wherein X is selected from the group consisting of: 
 (a) C 7 H 13  (cycloheptyl);    (b) (CH 3 ) 3 CCH 2 ; and    (c) CH 3 (CH 2 ) n , wherein 1≦n≦5.    
     
     
         14 . The method of  claim 1 , wherein the purine nucleotide is selected from the group consisting of: 
 compound 6a, compound 6b, compound 6c, compound 6d,    compound 6e, compound 7a, compound 7b, compound 7c,    compound 7d, compound 7e, compound 8a, compound 8b,    compound 8c, compound 8d, and compound 8e.    
     
     
         15 . The method of  claim 1 , wherein said enzyme is in a biological system, and said method results in a modulation of the level in said system of: 
 (a) a purine nucleotide;    (b) a purine nucleoside;    (c) a metabolite or derivative of (a) or (b); or    (d) any combination thereof.    
     
     
         16 . The method of  claim 1 , wherein said enzyme is in a biological system, and said method results in a modulation of the activity of a biological process in a said system, wherein said process is affected by the level in said system of: 
 (a) a purine nucleotide;    (b) a purine nucleoside;    (c) a metabolite or derivative of (a) or (b); or    (d) any combination thereof.    
     
     
         17 . The method of  claim 16 , wherein the biological process is aggregation and thrombogenecity.