The development of alternative antiepileptic drugs is needed as many patients remain untreated or often suffer from undesired side effects of the currently available therapeutics. Unselective sodium channel blockers have long been used as anticonvulsants; however, isoform selective inhibition of NaV1.6, while sparing NaV1.1, may offer a more effective and better tolerated approach to treatment. This presentation will describe the design, synthesis, and biological activity of a series of CNS penetrant aryl sulfonamides that inhibit NaV1.6 with isoform selectivity. Optimization focused on improving NaV1.6 potency, isoform selectivity over NaV1.1, and stability in human liver microsomes, while reducing P-gp efflux in order to increase CNS penetrance. These efforts ultimately led to the development of a brain penetrant tool compound that reduced seizure activity in a dose-dependent manner in an epilepsy model in mice, establishing an important proof-of-concept that state-dependent, selective NaV1.6 inhibitors provide efficacy in an in vivo model.

Optimization of aryl sulfonamides as CNS penetrant, isoform-selective NaV1.6 inhibitors with efficacy in mouse models of epilepsy

256th National Meeting (2018)

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