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

Thomas Ryckmans, Aisah Aubdool, Jennifer V. Bodkin, Peter Cox, Susan D. Brain, Thomas Dupont, Emma Fairman, Yoshinobu Hashizume, Naoko Ishii, Teruhisa Kato, Linda Kitching, Julie Newman, Kiyoyuki Omoto, David Rawson, Jade Strover

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4857 - 4859
Number of pages3
JournalBIOORGANIC AND MEDICINAL CHEMISTRY LETTERS
Volume21
Issue number16
DOIs
Publication statusPublished - 15 Aug 2011

Keywords

  • Animals
  • Ankyrins
  • Calcium Channels
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Edema
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Nerve Tissue Proteins
  • Pain
  • Piperazines
  • Pyrimidines
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • TRPC Cation Channels
  • Transient Receptor Potential Channels

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