Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective Na_V1.6 Inhibitors with Efficacy in Mouse...

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_V1.6 and Na_V1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of Na_V1.6, while sparing Na_V1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of Na_V1.2 may complement the anticonvulsant activity of Na_V1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective Na_V1.6 inhibitors, which also displayed potent block of Na_V1.2. Optimization focused on increasing selectivity over Na_V1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds 30-32, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.