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

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.

Human UDP-glucuronosyltransferase UGT1A4 forms tertiary N-glucuronides predominately with the energetically less favored tautomer of substituted 1H-indazole (benzpyrazole)

“…Animal liver S9 fractions were prepared as described before (Kittelmann et al 2003). Compound 1 was obtained from Novartis Pharmaceuticals Corporation, and the synthesis has been described (Rooney et al 2014).…”

“…In a joint medicinal chemistry program of our colleagues in the Horsham research center (U.K.) and from the Genomics Institute of the Novartis Research Foundation, San Diego, several TRPA1 antagonists for the treatment of pain were identified with IC 50 values as low as 15 nM (Rooney et al 2014). Early in vitro metabolism studies with rat or human hepatocytes suggested that the main human metabolite of a promising compound was a glucuronide.…”

Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists

“…Finally, Novartis identified the hit compound 5-(2-chlorophenyl)indazole (IC 50 = 1.23 μM) that was selected for further SAR optimization [127]. The replacement of the 2-chloro atom of the 5-phenyl ring with a CF 3 group combined with the optimization of 6-substitution resulted in a significant enhancement of TRPA1 inhibition potency; this is exemplified by derivative 48 (Figure 13, IC 50 = 15 nM).…”

“…The compound was orally effective also in a MO-induced allodynia model of visceral pain. In addition, 48 had no effects on body temperature although it was shown to interfere to some extent with noxious cold sensation [127].…”

Potassium tert-Butoxide Promoted Intramolecular Amination of 1-Aryl-2- (2-nitrobenzylidene)hydrazines: Efficient Synthesis of 1-Aryl-1H-indazoles

“…2 Furthermore, their antispermatogenic, 3 antitumor, 4 antiplatelet, 5 antimicrobial, 6 and A1 (TRPA1) antagonist 7 activities have been well documented. 2 Furthermore, their antispermatogenic, 3 antitumor, 4 antiplatelet, 5 antimicrobial, 6 and A1 (TRPA1) antagonist 7 activities have been well documented.…”