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

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• 作者：Lisa Rooney ; Agn猫s Vidal ; Anne-Marie D鈥橲ouza ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 26, 2014
• 年：2014
• 卷：57
• 期：12
• 页码：5129-5140
• 全文大小：465K
• ISSN：1520-4804

文摘

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