Abstract
Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / pharmacokinetics
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Acetamides / pharmacology
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Administration, Oral
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Analgesics / chemical synthesis*
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Animals
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Binding Sites
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Cell Line
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Formaldehyde
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Ganglia, Spinal / cytology
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Humans
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In Vitro Techniques
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Microsomes, Liver / metabolism
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NAV1.1 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins / antagonists & inhibitors*
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Neurons / drug effects
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Neurons / physiology
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Pain / drug therapy*
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Pain Measurement
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Patch-Clamp Techniques
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Rats
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Sodium Channel Blockers / chemical synthesis*
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Sodium Channel Blockers / pharmacokinetics
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Sodium Channel Blockers / pharmacology
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Sodium Channels
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Solubility
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Structure-Activity Relationship
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Tetrodotoxin / pharmacology
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Triazines / chemical synthesis*
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Triazines / pharmacokinetics
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Triazines / pharmacology
Substances
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Acetamides
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Analgesics
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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N-(2-methyl-3-(4-(4-(4-(trifluoromethoxy)benzyloxy)piperidin-1-yl)-1,3,5-triazin-2-ylamino)phenyl)acetamide
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NAV1.1 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins
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SCN1A protein, human
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Scn1a protein, rat
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Sodium Channel Blockers
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Sodium Channels
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Triazines
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Formaldehyde
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Tetrodotoxin