Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

  • Cell Rep. 2018 Sep 18;24(12):3133-3145. doi: 10.1016/j.celrep.2018.08.063.
Girish Bankar  1 ,  Samuel J Goodchild  1 ,  Sarah Howard  1 ,  Karen Nelkenbrecher  1 ,  Matthew Waldbrook  1 ,  Michelle Dourado  2 ,  Noah G Shuart  1 ,  Sophia Lin  1 ,  Clint Young  1 ,  Zhiwei Xie  1 ,  Kuldip Khakh  1 ,  Elaine Chang  1 ,  Luis E Sojo  1 ,  Andrea Lindgren  1 ,  Sultan Chowdhury  1 ,  Shannon Decker  1 ,  Michael Grimwood  1 ,  Jean-Christophe Andrez  1 ,  Christoph M Dehnhardt  1 ,  Jodie Pang  2 ,  Jae H Chang  2 ,  Brian S Safina  2 ,  Daniel P Sutherlin  2 ,  James P Johnson Jr  1 ,  David H Hackos  2 ,  C Lee Robinette  1 ,  Charles J Cohen  3
Affiliations
  • 1. Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada.
  • 2. Genentech, South San Francisco, CA 94080, USA.
  • 3. Xenon Pharmaceuticals, Burnaby, BC V5G 4W8, Canada. Electronic address: [email protected].
PMID: 30231997 DOI: 10.1016/j.celrep.2018.08.063
Abstract

Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among Sodium Channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.

Keywords
diabetic neuropathy; inherited erythromelalgia; pain; residence time; sodium channel.
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