Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel

Bioorg Med Chem Lett. 2011 Aug 15;21(16):4857-9. doi: 10.1016/j.bmcl.2011.06.035. Epub 2011 Jun 21.

Abstract

TrpA1 is an ion channel involved in nociceptive and inflammatory pain. It is implicated in the detection of chemical irritants through covalent binding to a cysteine-rich intracellular region of the protein. While performing an HTS of the Pfizer chemical collection, a class of pyrimidines emerged as a non-reactive, non-covalently binding family of agonists of the rat and human TrpA1 channel. Given the issues identified with the reference agonist Mustard Oil (MO) in screening, a new, non-covalently binding agonist was optimized and proved to be a superior agent to MO for screening purposes. Compound 16a (PF-4840154) is a potent, selective agonist of the rat and human TrpA1 channel and elicited TrpA1-mediated nocifensive behaviour in mouse.

MeSH terms

  • Animals
  • Ankyrins / agonists*
  • Calcium Channels
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Edema / drug therapy
  • Edema / physiopathology
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Nerve Tissue Proteins / agonists*
  • Pain / drug therapy
  • Pain / physiopathology
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • TRPA1 Cation Channel
  • TRPC Cation Channels
  • Transient Receptor Potential Channels / agonists*

Substances

  • Ankyrins
  • Calcium Channels
  • Nerve Tissue Proteins
  • PF 4840154
  • Piperazines
  • Pyrimidines
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • TRPC Cation Channels
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • Trpa1 protein, rat