Selective block of Na1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several Na1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC 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 IC. 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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Nonselective antagonists of voltage-gated sodium (Na V ) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels on excitatory neurons, primarily Na V 1.6 and Na V 1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of Na V 1.6, while sparing Na V 1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of Na V 1.2 may complement the anticonvulsant activity of Na V 1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective Na V 1.6 inhibitors, which also displayed potent block of Na V 1.2. Optimization focused on increasing selectivity over Na V 1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane Xreceptor liability. We obtained compounds 30−32, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.