Abstract
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
MeSH terms
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Analgesics / chemistry*
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Analgesics / therapeutic use*
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Animals
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Benzenesulfonamides
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Drug Discovery
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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HEK293 Cells
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Humans
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Male
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Mice
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NAV1.7 Voltage-Gated Sodium Channel / metabolism
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Pain / drug therapy*
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Pain / metabolism
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Piperidines / chemistry
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Sulfonamides / chemistry*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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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 / pharmacokinetics
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Voltage-Gated Sodium Channel Blockers / pharmacology
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Voltage-Gated Sodium Channel Blockers / therapeutic use*
Substances
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Analgesics
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NAV1.7 Voltage-Gated Sodium Channel
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Piperidines
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Sulfonamides
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Voltage-Gated Sodium Channel Blockers