Abstract
The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.
MeSH terms
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Analgesics, Non-Narcotic / chemical synthesis
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Analgesics, Non-Narcotic / chemistry*
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Analgesics, Non-Narcotic / pharmacology*
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Animals
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Furans / chemical synthesis
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Furans / chemistry*
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Furans / pharmacology*
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Humans
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Male
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Mice
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Neuralgia / drug therapy*
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Piperazines / chemical synthesis
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Piperazines / chemistry*
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Piperazines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Sodium Channel Blockers / chemical synthesis
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Sodium Channel Blockers / chemistry*
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Sodium Channel Blockers / pharmacology*
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Sodium Channels / drug effects*
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Structure-Activity Relationship
Substances
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Analgesics, Non-Narcotic
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Ether-A-Go-Go Potassium Channels
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Furans
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Piperazines
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Sodium Channel Blockers
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Sodium Channels