PubMed 24884675

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: TRP , TRPA , TRPA1

Title: Discovery, Optimization, and Biological Evaluation of 5-(2-(Trifluoromethyl)phenyl)indazoles as a Novel Class of Transient Receptor Potential A1 (TRPA1) Antagonists.

Authors: Lisa Rooney, Agnès Vidal, Anne-Marie D'Souza, Nick Devereux, Brian Masick, Valerie Boissel, Ryan West, Victoria Head, Rowan Stringer, Jianmin Lao, Matt J Petrus, Ardem Patapoutian, Mark Nash, Natalie Stoakley, Moh Panesar, J Martin Verkuyl, Andrew M Schumacher, H Michael Petrassi, David C Tully

Journal, date & volume: J. Med. Chem., 2014 Jun 26 , 57, 5129-40

PubMed link:

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.