Rooney, L, Vidal, A, D'Souza, AM, Devereux, N, Masick, B, Boissel, V, West, R, Head, V, Stringer, R, Lao, J, Petrus, MJ, Patapoutian, A, Nash, M, Stoakley, N, Panesar, M, Verkuyl, JM, Schumacher, AM, Petrassi, HM and Tully, DC (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. pp. 5129-5140.

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 muM. 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 muM), which has moderate oral bioavailability in rodents and demonstrates robust activity in vivo in several rodent models of inflammatory pain

Item Type:	Article
Additional Information:	NIBR author: Tully D institute: NIBR contributor address: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22746