Dual-Action Compounds Targeting Adenosine A2A Receptor and Adenosine Transporter for Prevention and Treatment of Neurodegenerative Diseases

Abstract

The present invention provides therapeutic agents for preventing and treating neurodegenerative diseases. These agents synergistically target both the adenosine A 2A receptor (A 2A R) and the equilibrative nucleoside transporter 1 (ENT1).

1 . A compound having an adenosine structural scaffold with variations at C-6 and C-5′ with the following structure 
       
         
           
           
               
               
           
         
         wherein n is 1 to 3, R 1  selected from the group consisting of (substituted)-benzene, polyarene and heterocycle, R 2  is selected from the group consisting of halogen, hydroxyl, alkoxy, azido, amino, (substituted)amino, amido, sulfanyl, sulfonyl, triazolyl, and cyano groups, and R 3  is selected from the group consisting of (substituted)carbonyl, carboxylate, (substituted)carbamide, cyano, (substituted)alkynyl, and (substituted)tetrazole groups. 
       
     
     
         2 . The compound according to  claim 1  having the structure of 
       
         
           
           
               
               
           
         
         wherein the (substituted) heterocycle contains 5- or 6-membered rings and the fused heterocycle contain nitrogen, oxygen or sulfur heteroatoms and the substituents is selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine and iodine), hydroxy, alkyl (1 to 6 carbons), trifluoromethyl, and (substituted)phenyl group. 
       
     
     
         3 . The compound of  claim 2  where the heterocycle is selected from the group consisting of pyrrole, furan, thiophene, pyridine, piperidine, piperazine, indole, benzofuran, benzothiophene, and quinoline. 
     
     
         4 . The compound according to  claim 1  having the structure of 
       
         
           
           
               
               
           
         
         The aromatic ring is selected from the group consisting of benzene, naphthalene, anthracene, phenanthrene, and pyrene; when n=1, the benzyl group may optionally have substituents selected from the group consisting of halogen (fluorine, chlorine, bromine and iodine), alkyl (methyl, ethyl, propyl, butyl and trifluoromethyl), phenyl, hydroxy, alkoxyl (OR where R═CH 3 , C 2 H 5 , C 3 H 7  and C 4 H 9 ), amino (NRR′ where R, R′ represent H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9  and phenyl), amido (NHCOR where R═CH 3 , C 2 H 5 , C 3 H 7  and C 4 H 9 ), nitro, sulfonate, alkanoyl (COR where R═H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9  and phenyl), and carboxylate (CO 2 R where R═H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9  and phenyl). 
       
     
     
         5 . The compound according to  claim 1  having the structure of 
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of hydrogen, alkyl (1 to 4 carbons), and (substituted)phenyl groups. 
       
     
     
         6 . The compound according to  claim 1  having the structure of 
       
         
           
           
               
               
           
         
         wherein R 4  is selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine and iodine), hydroxy, alkyl (1 to 6 carbons), trifluoromethyl, and (substituted) phenyl group. 
       
     
     
         7 . The compound according to  claim 1  having the structure of 
       
         
           
           
               
               
           
         
         wherein R 5  is selected from the group consisting of hydrogen and alkyl (1 to 4 carbons) groups. 
       
     
     
         8 . The compound according to  claim 4  having the structure of 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of H, halogen (F, Cl, Br, and I), alkyl (1 to 4 carbons, trifluoromethyl, phenyl, hydroxyl, alkoxy (1 to 4 carbons), (substituted)amino, (substituted)amido, nitro, sulfonate, carbonyl, and carboxylate groups located at ortho-, meta- or para-positions, and wherein x is 1 to 5. 
       
     
     
         9 . A method for treating neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of at least one of the compounds of  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein the neurodegenerative disease is a protein-misfolding disease. 
     
     
         11 . The method of  claim 9  wherein the neurodegenerative disease is Huntington's disease. 
     
     
         12 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . A compound having the following structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A method for treating neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of at least one of the compounds of  claim 13 . 
     
     
         15 . The method of  claim 14  wherein the neurodegenerative disease is an protein-misfolding disease. 
     
     
         16 . The method of  claim 14  wherein the neurodegenerative disease is Huntington's disease.