Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia
David R. Witty, Giuseppe Alvaro, Dominique Derjean, Gerard M.P. Giblin, Kevin P. Gunn, Charles H. Large, David T. MacPherson, Valérie Morisset, Davina E. OWEN, Joanne Palmer, François Rugiero, Simon Tate, Christopher A. Hinckley, Himanshu Naik
Abstract
Drugs that block voltage-gated sodium channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics ( Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV 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.