Structure-Activity Relationship of Heterocyclic P2Y(14) Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres

A known zwitterionic, heterocyclic P2Y(14)R 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...

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Published inJournal of medicinal chemistry Vol. 64; no. 8; pp. 5099 - 5122
Main Authors Jung, Young-Hwan, Salmaso, Veronica, Wen, Zhiwei, Bennett, John M., Phung, Ngan B., Lieberman, David, Gopinatth, Varun, Randle, John C. R., Chen, Zhoumou, Salvemini, Daniela, Karcz, Tadeusz P., Cook, Donald N., Jacobson, Kenneth A.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 22.04.2021
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
MOLECULAR-DYNAMICS
PROTEIN
DOCKING
FORCE-FIELD
AUTOMATION
PARAMETERS
STRUCTURE-BASED DESIGN
ATOM
LIPOPHILICITY
AGONIST
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Summary:A known zwitterionic, heterocyclic P2Y(14)R 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 P2Y(14)R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3yl) 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 cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y(14)R antagonists for in vivo application.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00164