Synthesis and structure-activity relationships of a new set of 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as adenosine receptor antagonists.

In a previous paper (Colotta V. et al., J. Med. Chem. 2000, 43, 1158), we reported the synthesis and the binding activity of some 4-oxo (A) and 4-amino (B) substituted 1,2,4-triazolo[4,3-a]quinoxalin-1-ones, bearing different substituents on the appended 2-phenyl ring (region 1), some of which were potent and selective A1 or A3 antagonists. To further investigate the SAR in this class of antagonists, in the present paper some 2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives of both series A and B, bearing simple substituents on the benzofused moiety (region 2), are reported. The binding data at bovine A1 (bA1) and A2A(bA2A) and at human A3 (hA3) adenosine receptors (ARs) show that in series A (compounds 1, 4–11) the presence of substituents on the benzofused moiety is, in general, not advantageous for anchoring at all three AR subtypes, while within series B (compounds 12–21) it exerts a beneficial effect for both bA1 and hA3 AR affinities which span the low nanomolar range. In particular, among the 4-amino derivatives 12–21, the 8-chloro-6-nitro (compound 17) and the 6-nitro (compound 18) substitutions afford, respectively, the highest bA1 and hA3 AR affinity. Moreover, compound 18, additionally investigated in binding assays at human A1 (hA1) receptors, shows a 183-fold selectivity for hA3 versus hA1 receptors. Finally, the SAR studies provide some new insights about the steric and lipophilic requirements of the hA3 receptor binding pocket which accommodates the benzofused moiety of our 4-amino-triazoloquinoxalin- 1-one derivatives.