Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel |
| |
Authors: | Ryckmans Thomas Aubdool Aisah A Bodkin Jennifer V Cox Peter Brain Susan D Dupont Thomas Fairman Emma Hashizume Yoshinobu Ishii Naoko Kato Teruhisa Kitching Linda Newman Julie Omoto Kiyoyuki Rawson David Strover Jade |
| |
Institution: | a Pfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich, Kent CT139NJ, United Kingdom b Cardiovascular Division, King’s College London, Franklin-Wilkins Building, Waterloo Campus, London SE1 9NH, United Kingdom c Pfizer Discovery Biology, Ramsgate Road, Sandwich, Kent CT139NJ, United Kingdom d Pfizer Global Research and Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan |
| |
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. |
| |
Keywords: | TrPpA1 Agonist Pain Nociception HTS TrpA1 knockout |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|