2025/08/12 by Romain Siegrist, Olivier Bezençon, Caroline Deymier +6 · 1 voice
Biochemistry, Genetics and Molecular Biology · Engineering · Neuroscience · #Innovative Microfluidic and Catalytic Techniques Innovation #Neuroscience and Neural Engineering #Phosphodiesterase function and regulation
paper · doi:10.1021/acs.jmedchem.5c00945
openalex publication_date 2025/08/12 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
Abstract 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 31 (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 KV7 potassium channels, a mechanism consistent with the modulation of neuronal excitability.