The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A2Breceptor

A new series of amino-3,5-dicyanopyridines (3-28) as analogues of the adenosine hA2Breceptor agonist BAY60-6583 (compound 1) was synthesized. All the compounds that interact with the hA2Badenosine receptor display EC50values in the range 9-350 nM behaving as partial agonists, with the only exception being the 2-[4-(4-acetamidophenyl)-6-amino-3,5-dicyanopyridin-2-yl]thioacetamide (8) which shows a full agonist profile. Moreover, the 2-[(1H-imidazol-2-yl)methylthio)]-6-amino-4-(4-cyclopropylmethoxy-phenyl)pyridine-3,5-dicarbonitrile (15) turns out to be 3-fold more active than 1 although less selective. This result can be considered a real breakthrough due to the currently limited number of non-adenosine hA2BAR agonists reported in literature. To simulate the binding mode of nucleoside and non-nucleoside agonists at the hA2BAR, molecular docking studies were performed at homology models of this AR subtype developed by using two crystal structures of agonist-bound A2AAR as templates. These investigations allowed us to represent a hypothetical binding mode of hA2Breceptor agonists belonging to the amino-3,5-dicyanopyridine series and to rationalize the observed SAR.