Selective Nav1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain


Cell Reports


Girish Bankar, Samuel J. Goodchild, Sarah Howard, Karen Nelkenbrecher, Matthew Waldbrook, Michelle Dourado,Noah G. Shuart, Sophia Lin, Clint Young, Zhiwei Xie, Kuldip Khakh, Elaine Chang, Luis E. Sojo, Andrea Lindgren,Sultan Chowdhury, Shannon Decker, Michael Grimwood, Jean-Christophe Andrez, Christoph M. Dehnhardt,Jodie Pang, Jae H. Chang, Brian S. Safina, Daniel P. Sutherlin, James P. Johnson, Jr., David H. Hackos,C. Lee Robinette, and Charles J. Cohen



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 IC50for channel block. Here, we report a target engagement assay using transgenic mice that have 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.

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