Exploring the directionality of 5-substitutions in a new series of 5-alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine as a strategy to design novel human A3 adenosine receptor antagonists

Article abstract of DOI:10.1021/jm300899q

The structure-activity relationship (SAR) of new 5-alkylaminopyrazolo[4,3- e]1,2,4-triazolo[1,5-c]pyrimidines as antagonists of the A₃ adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A₃ AR. All the synthesized compounds showed affinity for the hA ₃ AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (S) α-phenylethylamino moiety at the 5 position (26, K_i hA₃ = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo[4,3-e]1,2,4- triazolo[1,5-c]pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N⁵ position toward the extracellular environment.