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

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

来源：Journal of Medicinal Chemistry, 2014, 57(12): 5129-5140.

DOI：10.1021/jm401986p

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

• 出版日期2014-6-26