Discovery, optimization, and biological evaluation of 5-(2-(trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists
| Autor: | Nicholas James Devereux, Anne-Marie D’Souza, Valerie Boissel, Vidal Agnes, Mark Nash, Ardem Patapoutian, Ryan West, J. Martin Verkuyl, Andrew M. Schumacher, Brian T. Masick, Victoria Head, H. Michael Petrassi, Rowan Stringer, Lisa Ann Rooney, Natalie Stoakley, Moh Panesar, David C. Tully, Jianmin Lao, Matt Petrus |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Indazoles Stereochemistry Freund's Adjuvant Anti-Inflammatory Agents Administration Oral Biological Availability Nerve Tissue Proteins CHO Cells Ring (chemistry) chemistry.chemical_compound Structure-Activity Relationship Cricetulus Transient Receptor Potential Channels Species Specificity In vivo Drug Discovery Animals Humans Plant Oils Rats Wistar IC50 TRPA1 Cation Channel TRPC Cation Channels Indazole Analgesics Trifluoromethyl Antagonist Hit to lead In vitro Mice Inbred C57BL chemistry Hyperalgesia Molecular Medicine Calcium Channels Mustard Plant |
| Zdroj: | Journal of medicinal chemistry. 57(12) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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