Rooney, Lisa, D'Souza, Anne-Marie, Devereux, Nicholas, Boissel, Valerie, West, Ryan, Stringer, Rowan, Head, Victoria, Nash, Mark, Tully, David, Petrassi, Hank, Masick, Brian, Lao, Jianmin, Vidal-Biggart, Agnes, Petrus, Matthew, Schumacher, Andrew, Verkuijl, Martin, Stoakley, Natalie, Panesar, Moh and Patapoutian, Ardem (2014) Discovery, optimization, and biological evaluation of 5-(2- (trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists. Journal of Medicinal Chemistry, 57 (12). pp. 5129-5140. ISSN 1520-4804

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. © 2014 American Chemical Society.

Item Type:	Article
Date Deposited:	14 Mar 2018 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/21717