Session: Posters:

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 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 proven cleavable by liver esterase, and efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y₁₄R antagonists for in vivo application.

Docking pose of compound 29 (A), in green, and compound 32 (B), in orange, at the P2Y₁₄R structure (gray), obtained by MD-refined homology modeling using an agonist-bound P2Y₁₂R structure (PDB ID: 4PXZ) as template."/>

Docking pose of compound 29 (A), in green, and compound 32 (B), in orange, at the P2Y₁₄R structure (gray), obtained by MD-refined homology modeling using an agonist-bound P2Y₁₂R structure (PDB ID: 4PXZ) as template.

Dr. Young-Hwan Jung

Postdoctoral researcher, National institutes of Health

Appearances