title: Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel.
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.
authors: Pfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich, Kent CT139NJ, United Kingdom. thomas.ryckmans@pfizer.com
authors: Thomas
authors: T
authors: Ryckmans
authors: Aisah A
authors: AA
authors: Aubdool
authors: Jennifer V
authors: JV
authors: Bodkin
authors: Peter
authors: P
authors: Cox
authors: Susan D
authors: SD
authors: Brain
authors: Thomas
authors: T
authors: Dupont
authors: Emma
authors: E
authors: Fairman
authors: Yoshinobu
authors: Y
authors: Hashizume
authors: Naoko
authors: N
authors: Ishii
authors: Teruhisa
authors: T
authors: Kato
authors: Linda
authors: L
authors: Kitching
authors: Julie
authors: J
authors: Newman
authors: Kiyoyuki
authors: K
authors: Omoto
authors: David
authors: D
authors: Rawson
authors: Jade
authors: J
authors: Strover
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000819:agonists*; D015220:Calcium Channels; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004487:Edema / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000819:agonists*; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels / Q000819:agonists*
chemical_list: D017487:Ankyrins; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; C568086:PF 4840154; D010879:Piperazines; D011743:Pyrimidines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat