Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.

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.

• Authors: David R Witty, Giuseppe Alvaro, Dominique Derjean, Gerard M P Giblin, Kevin Gunn, Charles Large, David T Macpherson, Valerie Morisset, Davina Owen, Joanne Palmer, Francois Rugiero, Simon Tate, Christopher A Hinckley, Himanshu Naik
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 11 Issue 9 Pg. 1678-1687 (Sep 10 2020) ISSN: 1948-5875 [Print] United States
• PMID: 32945812 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 American Chemical Society.