Development of Novel Small-Molecule Targeting SCN1A-Associated Severe Myoclonic Epilepsy of Infancy.

Abstract

Severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome), which is mainly caused by themutation, is a severe epileptic encephalopathy that manifests in infancy and leads to intractable seizures and developmental impairment. To discover new therapeutic chemotypes, we established a Nav1.1 () KO zebrafish model for chemical screening and identified novel 1,3,4-oxadiazol-2(3)-one derivatives. Among them, compoundshowed the most potent antiseizure efficacy in zebrafish behavioral assays and significantly reduced locomotion-related seizure parameters compared with repositioned drugs. Inmice,reduced seizure severity, delayed onset, and suppressed hyperactivity. Notably,normalized pathological spike and burst activity in SMEI patient-derived iPSC neurons. Mechanistically,appears to elevate 5-HT levels via TPH2 upregulation. It demonstrated reasonable BBB penetration, favorable oral PK, and good safety without notable hERG inhibition, cytotoxicity, mutagenicity, or acute toxicity. Taken together, compoundshows promise as a therapeutic agent for SMEI.