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

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. [Display omitted] •Aconitine-induced pain in IEM mice enables assay for target engagement of hNaV1.7•Acylsulfonamides inhibit pain at low multiples of the IC50 for inhibition of NaV1.7•Improvement versus arylsulfonamides correlates with longer residency time on NaV1.7•Repeat dosing of acylsulfonamides results in a 10-fold decrease in EC50 for analgesia Bankar et al. show that acylsulfonamides produce analgesic activity at low multiples of the IC50 for inhibition of NaV1.7, in contrast to studies with arylsulfonamides that required >10 times the IC50. The improvement correlates with longer residency time on the target channels.