Exploring the Directionality of 5‑Substitutions in a New Series of 5‑Alkylaminopyrazolo[4,3‑<i>e</i>]1,2,4-triazolo[1,5‑<i>c</i>]pyrimidine as a Strategy To Design Novel Human A₃ Adenosine Receptor Antagonists.

Abstract

The structure–activity relationship (SAR) of new 5-alkylaminopyrazolo­[4,3-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­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 hA₃ AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (<i>S</i>) α-phenylethylamino moiety at the 5 position (<b>26</b>, <i>K</i>_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-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N⁵ position toward the extracellular environment