The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A2B receptor

Abstract

A new series of amino-3,5-dicyanopyridines (3–28) as analogues of the adenosine hA2B receptor agonist BAY60-6583 (compound 1) was synthesized. All the compounds that interact with the hA2B adenosine receptor display EC50 values 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]thio}acetamide (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 hA2B AR agonists reported in literature. To simulate the binding mode of nucleoside and non-nucleoside agonists at the hA2B AR, molecular docking studies were performed at homology models of this AR subtype developed by using two crystal structures of agonist-bound A2A AR as templates. These investigations allowed us to represent a hypothetical binding mode of hA2B receptor agonists belonging to the amino-3,5-dicyanopyridine series and to rationalize the observed SAR.