Structure-Activity Relationship of Heterocyclic P2Y Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres.

A known zwitterionic, heterocyclic P2YR antagonist was substituted with diverse groups on the central phenyl and terminal piperidine moieties, following a computational selection process. The most potent analogues contained an uncharged piperidine bioisostere, prescreened in silico, while an aza-scan (central phenyl ring) reduced P2YR affinity. Piperidine amide , 3-aminopropynyl , and 5-(hydroxymethyl)isoxazol-3-yl) congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (; MRS4654; IC, 15 nM) and less active phenylamide-containing () scaffolds. Thus, a zwitterion was nonessential for receptor binding, and molecular docking and dynamics probed the hydroxymethylisoxazole interaction with extracellular loops. Also, amidomethyl ester prodrugs were explored to reversibly block the conserved carboxylate group to provide neutral analogues, which were cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2YR antagonists for in vivo application.