Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 3: Structure-activity relationships of pyrropyrazolone derivatives

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127636. doi: 10.1016/j.bmcl.2020.127636. Epub 2020 Oct 22.

Abstract

The P2X3 receptor is an attractive target for the treatment of pain and chronic coughing, and thus P2X3 antagonists have been developed as new therapeutic drugs. We previously reported selective P2X3 receptor antagonists by derivatization of hit compound 1. As a result, we identified hit compound 3, the structure of which was similar to hit compound 1. On the basis of SAR studies of hit compound 1, we modified hit compound 3 and compound 42 was identified as having analgesic efficacy by oral administration.

Keywords: Ion channels; P2X3 receptor antagonists; Pain; Purinergic receptors; Pyrrolopyrazolone derivatives.

MeSH terms

  • Drug Discovery
  • Humans
  • Molecular Docking Simulation
  • Purinergic P2X Receptor Antagonists / chemistry*
  • Purinergic P2X Receptor Antagonists / pharmacology*
  • Pyrazolones / chemistry*
  • Pyrazolones / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Receptors, Purinergic P2X3 / chemistry
  • Receptors, Purinergic P2X3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Purinergic P2X Receptor Antagonists
  • Pyrazolones
  • Pyrroles
  • Receptors, Purinergic P2X3
  • pyrroline
  • pyrazolone