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; rₚᵣₑd ²=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.