Discovery of the First Orally Available, Selective K_Na1.1 Inhibitor: <i>In Vitro</i> and <i>In Vivo</i> Activity of an Oxadiazole Series

Abstract

The gene <i>KCNT1</i> encodes the sodium-activated potassium channel K_Na1.1 (Slack, Slo2.2). Variants in the <i>KCNT1</i> 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 <i>KCNT1</i>-related disease are absent, and novel therapies are urgently required. We describe the development of a novel class of oxadiazole K_Na1.1 inhibitors, leading to the discovery of compound <b>31</b> that reduced seizures and interictal spikes in a mouse model of <i>KCNT1</i> GoF.