Discovery of the First Orally Available, Selective K1.1 Inhibitor: and Activity of an Oxadiazole Series.

The gene encodes the sodium-activated potassium channel K1.1 (Slack, Slo2.2). Variants in the gene induce a gain-of-function (GoF) phenotype in ionic currents and cause a spectrum of intractable neurological disorders in infants and children, including epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Effective treatment options for -related disease are absent, and novel therapies are urgently required. We describe the development of a novel class of oxadiazole K1.1 inhibitors, leading to the discovery of compound that reduced seizures and interictal spikes in a mouse model of GoF.