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

A high throughput screening campaign identified 5-(2-chlorophenyl)­indazole compound <b>4</b> 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 <b>31</b>, 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

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP₂ Receptor Antagonist for Treatment of Asthma

Further optimization of an initial DP₂ receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)­benzyl)-1<i>H</i>-pyrrolo­[2,3-<i>b</i>]­pyridin-3-yl)­acetic acid (compound <b>11</b>, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma