[Image: see text] Drugs that block voltage-gated sodium channels (Na(V)s) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.2010941342420298965; Expert Opin. Ther. Pat.20102075577920384535). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved Na(V) blocking drugs (Comprehensive Medicinal Chemistry III; Elsevier, 2017; pp 131−175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.