Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.

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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.