Structure–Activity Relationship of Heterocyclic P2Y14 Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres
Autor: | Kenneth A. Jacobson, Donald N. Cook, Tadeusz P Karcz, John C R Randle, John M. Bennett, Varun Gopinatth, Zhiwei Wen, Ngan B. Phung, Daniela Salvemini, Young-Hwan Jung, David I. Lieberman, Veronica Salmaso, Zhoumou Chen |
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Rok vydání: | 2021 |
Předmět: |
Stereochemistry
Triazole Molecular Dynamics Simulation 01 natural sciences Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Piperidines Animals Binding Sites Disease Models Animal Drug Design Humans Molecular Docking Simulation Neuralgia Prodrugs Purinergic P2 Receptor Antagonists Receptors Purinergic P2 Solubility Triazoles Amide Receptors Drug Discovery Structure–activity relationship Hydroxymethyl Carboxylate 030304 developmental biology 0303 health sciences Purinergic P2 Animal 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Zwitterion Disease Models Molecular Medicine Bioisostere Piperidine |
Zdroj: | Journal of Medicinal Chemistry. 64:5099-5122 |
ISSN: | 1520-4804 0022-2623 |
Popis: | 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 cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application. |
Databáze: | OpenAIRE |
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