Exploration of Alternative Scaffolds for P2Y 14 Receptor Antagonists Containing a Biaryl Core

J Med Chem. 2020 Sep 10;63(17):9563-9589. doi: 10.1021/acs.jmedchem.0c00745. Epub 2020 Aug 6.

Abstract

Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y14 receptor (P2Y14R) antagonists were synthesized, and affinity was measured in P2Y14R-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y14R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC50 ≈ 20 nM at hP2Y14R/mP2Y14R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y14R antagonist structure-activity relationship, introducing diverse physical-chemical properties.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Neuralgia / drug therapy
  • Protein Conformation
  • Purinergic P2 Receptor Antagonists / chemistry*
  • Purinergic P2 Receptor Antagonists / metabolism
  • Purinergic P2 Receptor Antagonists / pharmacology*
  • Purinergic P2 Receptor Antagonists / therapeutic use
  • Receptors, Purinergic P2 / chemistry
  • Receptors, Purinergic P2 / metabolism*
  • Solubility
  • Structure-Activity Relationship
  • Triazoles / chemistry*
  • Triazoles / metabolism
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use

Substances

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