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Discovery, optimization, and biological evaluation of 5-(2- (trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists

Rooney, Lisa and D'Souza, Anne-Marie and Devereux, Nicholas and Boissel, Valerie and West, Ryan and Stringer, Rowan and Head, Victoria and Nash, Mark and Tully, David and Petrassi, Hank and Masick, Brian and Lao, Jianmin and Vidal-Biggart, Agnes and Petrus, Matthew and Schumacher, Andrew and Verkuijl, Martin and Stoakley, Natalie and 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/20363

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