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.
MeSH terms
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Administration, Oral
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Analgesics / chemistry
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology
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Biological Availability
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CHO Cells
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Calcium Channels
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Cricetulus
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Freund's Adjuvant
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Humans
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Hyperalgesia / chemically induced
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Hyperalgesia / drug therapy
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Indazoles / chemistry*
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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Male
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Mice, Inbred C57BL
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Mustard Plant
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Nerve Tissue Proteins / antagonists & inhibitors*
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Plant Oils
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Rats, Wistar
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Species Specificity
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Structure-Activity Relationship
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TRPA1 Cation Channel
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TRPC Cation Channels / antagonists & inhibitors
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Transient Receptor Potential Channels / antagonists & inhibitors*
Substances
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6-methyl-5-(2-(trifluoromethyl)phenyl)-1H-indazole
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Analgesics
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Anti-Inflammatory Agents
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Calcium Channels
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Indazoles
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Nerve Tissue Proteins
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Plant Oils
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TRPA1 Cation Channel
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TRPA1 protein, human
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TRPC Cation Channels
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Transient Receptor Potential Channels
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Trpa1 protein, mouse
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Trpa1 protein, rat
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Freund's Adjuvant
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mustard oil