Synthesis and Structure-Activity Relationships of 4-Cycloalkylamino-1,2,4-triazolo[4,3-a]quinoxalin-1-one Derivatives as A 1 and A3 Adenosine Receptor Antagonists

Abstract

In a previous paper (Colotta V. et al., J. Med. Chem. 2000, 43, 1158-1164) we reported the synthesis and binding activity of 4-cycloalkylamino-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, differently substituted on the appended 2-phenyl ring, some of which were potent and selective A1 adenosine receptor (AR) antagonists. In the present paper several 4-cycloalkylamino-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives (1-11), bearing simple substituents on the benzofused moiety, are reported. The binding data of bovine A1 and A2A and human A3 AR show that we have obtained highly potent A1 AR antagonists. In particular, the 4-cyclohexylamino derivatives 1-5 show higher A1 vs A2A selectivity than the parent compound A, which lacks substituents on the benzofused moiety. Moreover, compounds 1-11 display, in general, good A3 AR affinity. Finally, SAR studies provide some new insights about the steric requirements of the A3 receptor pocket, which accommodates the benzofused moiety of our 4-amino-triazoloquinoxalin-1-one derivatives.