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. 2018 Sep 18;24(12):3133-3145.
doi: 10.1016/j.celrep.2018.08.063.

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

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
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Free article

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

Girish Bankar et al. Cell Rep. .
Free article

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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