title: Discovery, optimization, and biological evaluation of 5-(2-(trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists.
abstract: A high throughput screening campaign identified 5-(2-chlorophenyl)indazole compound 4 as an antagonist of the transient receptor potential A1 (TRPA1) ion channel with IC50 = 1.23 μM. Hit to lead medicinal chemistry optimization established the SAR around the indazole ring system, demonstrating that a trifluoromethyl group at the 2-position of the phenyl ring in combination with various substituents at the 6-position of the indazole ring greatly contributed to improvements in vitro activity. Further lead optimization resulted in the identification of compound 31, a potent and selective antagonist of TRPA1 in vitro (IC50 = 0.015 μM), which has moderate oral bioavailability in rodents and demonstrates robust activity in vivo in several rodent models of inflammatory pain.
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rooney
authors.forename: Agnès
authors.initials: A
authors.lastname: Vidal
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: D'Souza
authors.forename: Nick
authors.initials: N
authors.lastname: Devereux
authors.forename: Brian
authors.initials: B
authors.lastname: Masick
authors.forename: Valerie
authors.initials: V
authors.lastname: Boissel
authors.forename: Ryan
authors.initials: R
authors.lastname: West
authors.forename: Victoria
authors.initials: V
authors.lastname: Head
authors.forename: Rowan
authors.initials: R
authors.lastname: Stringer
authors.forename: Jianmin
authors.initials: J
authors.lastname: Lao
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Petrus
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
authors.forename: Mark
authors.initials: M
authors.lastname: Nash
authors.forename: Natalie
authors.initials: N
authors.lastname: Stoakley
authors.forename: Moh
authors.initials: M
authors.lastname: Panesar
authors.forename: J Martin
authors.initials: JM
authors.lastname: Verkuyl
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schumacher
authors.forename: H Michael
authors.initials: HM
authors.lastname: Petrassi
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D015220:Calcium Channels; D003412:Cricetulus; D005620:Freund's Adjuvant; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007191:Indazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009149:Mustard Plant; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010938:Plant Oils; D017208:Rats, Wistar; D013045:Species Specificity; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors*
chemical_list: C000591340:6-methyl-5-(2-(trifluoromethyl)phenyl)-1H-indazole; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D015220:Calcium Channels; D007191:Indazoles; D009419:Nerve Tissue Proteins; D010938:Plant Oils; 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; D005620:Freund's Adjuvant; C027793:mustard oil