Discovery and In-Vivo Characterization of K_v7 Channel Openers through a Phenotypic Approach

Despite the availability of approximately 30 antiseizure drugs (ASDs), epilepsy remains a major unmet clinical need, with approximately 30% of epileptic patients experiencing uncontrolled seizures despite an adequately chosen treatment. Polypharmacology is a common feature of many ASDs and polypharmacy is a usual practice to treat epileptic patients. Several approved ASDs were originally discovered through phenotypic screening in rodent models of seizures. To overcome the technical and ethical challenges associated with animal testing, we developed an in vitro assay that recapitulates seizure-related neuronal hyperexcitability phenotypes in a dish. Using this unbiased assay, a new class of urea compounds was discovered. Through optimization, compound <b>31</b> (IDOR-1104-0086) was identified as an orally bioavailable and brain-penetrant compound with in vivo efficacy in two rodent models of epilepsy and a favorable tolerability profile. Target deconvolution revealed that these ureas exert their antiseizure effects through activation of K_V7 potassium channels, a mechanism consistent with the modulation of neuronal excitability.