4-amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as new potent and selective human A(3) adenosine receptor antagonists. synthesis, pharmacological evaluation, and ligand-receptor modeling studies

摘要

A structural investigation on some 4-amido-2-phenyl-1,2-dihydro-1,2,4-triazolo[ 4,3-a] quinoxalin-1-one derivatives, designed as human A(3) adenosine receptor ( hA(3) AR) antagonists, is described. In the new derivatives, some acyl residues with different steric bulk were introduced on the 4-amino group, and their combination with the 4-methoxy group on the 2-phenyl moiety, and/or the 6-nitro/6-amino substituent on the fused benzo ring, was also evaluated. Most of the new derivatives were potent and selective hA(3) AR antagonists. SAR analysis showed that hindering and lipophilic acyl moieties not only are well tolerated but even ameliorate the hA(3) affinity. Interestingly, the 4-methoxy substituent on the appended 2-phenyl moiety, as well as the 6-amino group, always exerted a positive effect, shifting the affinity toward the hA(3) receptor subtype. In contrast, the 6-nitro substituent exerted a variable effect. An intensive molecular modeling investigation was performed to rationalize the experimental SAR findings.