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

J Med Chem. 2021 Apr 22;64(8):5099-5122. doi: 10.1021/acs.jmedchem.1c00164. Epub 2021 Mar 31.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Binding Sites
  • Disease Models, Animal
  • Drug Design
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Neuralgia / drug therapy
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Prodrugs / chemistry
  • Prodrugs / metabolism
  • Purinergic P2 Receptor Antagonists / chemistry*
  • Purinergic P2 Receptor Antagonists / metabolism
  • Purinergic P2 Receptor Antagonists / therapeutic use
  • Receptors, Purinergic P2 / chemistry
  • Receptors, Purinergic P2 / genetics
  • Receptors, Purinergic P2 / metabolism*
  • Solubility
  • Structure-Activity Relationship
  • Triazoles / chemistry

Substances

  • P2Y14 receptor, human
  • Piperidines
  • Prodrugs
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2
  • Triazoles