Abstract
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.
MeSH terms
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Animals
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Drug Evaluation, Preclinical
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HEK293 Cells
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Half-Life
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Humans
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Hyperalgesia / drug therapy
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Hyperalgesia / pathology
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Indazoles / chemistry*
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Indoles / chemistry*
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Male
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Mice
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NAV1.7 Voltage-Gated Sodium Channel / chemistry*
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NAV1.7 Voltage-Gated Sodium Channel / metabolism
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Neuralgia / drug therapy*
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Neuralgia / pathology
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Patch-Clamp Techniques
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Structure-Activity Relationship
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Sulfonamides / chemistry*
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Sulfonamides / metabolism
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Sulfonamides / therapeutic use
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Voltage-Gated Sodium Channel Blockers / chemistry
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Voltage-Gated Sodium Channel Blockers / metabolism
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Voltage-Gated Sodium Channel Blockers / therapeutic use*
Substances
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Indazoles
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Indoles
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NAV1.7 Voltage-Gated Sodium Channel
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Sulfonamides
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Voltage-Gated Sodium Channel Blockers