Despite an abundance of available antiepileptic drugs (AEDs), there is a significant unmet medical need as many patients are refractory to current available therapeutics or often suffer from undesired side effects. Inhibitors of voltage gated sodium channels (NaV) have long been a mainstay of the anti-seizure pharmacopeia. Classic NaV inhibitors, including phenytoin and carbamazepine, are not selective and block all NaV subtypes indiscriminately, and their utility is often reduced by relatively narrow therapeutic indices. Adult central nervous system (CNS) neurons primarily express three NaVs: NaV1.1 (SCN1A), NaV1.2 (SCN2A), and NaV1.6 (SCN8A). While NaV1.6 and NaV1.2 are highly expressed in excitatory neurons, NaV1.1 is primarily expressed in GABAergic inhibitory interneurons. It is believed that inhibition of Nav1.1 is pro-convulsant, as indicated by the seizure phenotype of SCN1A heterozygous null patients who suffer from Dravet Syndrome. Inhibition of NaV1.5, the cardiac sodium channel, introduces additional risk for non-selective compounds. On the other hand, block of NaVs expressed in excitatory neurons, in particular NaV1.6, can be linked to anticonvulsant activity. We discovered a series of zwitterionic aryl sulfonamides as NaV1.6 blockers with excellent isoform selectivity, in particular over NaV1.1 and NaV1.5, and that we hypothesize will provide greater potential for efficacy and an improved therapeutic index. We report on our multi-parameter optimization strategy to augment potency, metabolic stability and CNS penetration of this series. Structural modifications allowed for tuning of the NaV1.6/NaV1.2 selectivity profile. We report on the anticonvulsant activity of our NaV1.6 inhibitors in a seizure model employing a heterozygous mouse with the incorporation of a gain-of-function mutation in the NaV1.6 channel (N1768D). This mutation in humans is one of the hyper-excitable etiologies of the childhood epilepsy, Early Infantile Epileptic Encephalopathy type 13 (EIEE13).

Nav1.6 inhibitors: Approach to treat severe childhood epilepsies

2019 Fall National Meeting

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