Pharmacophore elucidation for a new series of 2-aryl-pyrazolo-triazolo-pyrimidines as potent human A3 adenosine receptor antagonists

A ligand-based pharmacophore was obtained for a new series of 2-unsubstituted and 2-(para-substituted)phenyl-pyrazolo-triazolo-pyrimidines as potent human A3 adenosine receptor antagonists. Through comparative molecular field analysis-based quantitative structure–activity relationship studies, structural features at the N5-, N8- and C2-positions of the tricyclic nucleus were deeply investigated, with emphasis given to the unprecedentedly explored C2-position. The resulting model showed good correlation and predictability (r2 = 0.936; q2 = 0.703; rpred2=0.663). Overall, the contribution of steric effect was found relatively more predominant for the optimal interaction of these antagonists to the human A3 receptor.

Graphical abstractThe ligand-based pharmacophore elucidation performed on 2-aryl-pyrazolo-triazolo-pyrimidines as potent hA3 adenosine receptor antagonists has provided new insights on the structural characteristics deemed critical for the affinity at the hA3 adenosine receptor.Figure optionsDownload full-size imageDownload as PowerPoint slide