Discovery, optimization, and biological evaluation of 5-(2-(trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists.
J Med Chem
; 57(12): 5129-40, 2014 Jun 26.
Article
in En
| MEDLINE
| ID: mdl-24884675
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.
Full text:
1
Database:
MEDLINE
Main subject:
Transient Receptor Potential Channels
/
Indazoles
/
Nerve Tissue Proteins
Language:
En
Journal:
J Med Chem
Year:
2014
Type:
Article
Affiliation country:
United States