Structure-Activity Relationship of Heterocyclic P2Y₁₄ Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres.

ABSTRACT: A known zwitterionic, heterocyclic P2Y₁₄R antagonist 3a 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 P2Y₁₄R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (32; MRS4654; IC₅₀, 15 nM) and less active phenylamide-containing (33) scaffolds. Thus, a zwitterion was nonessential for receptor b

SUBMITTER: Jung YH 

PROVIDER: S-EPMC8317135 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature