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

Severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome),
which
is mainly caused by the SCN1A mutation, 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 (scn1lab) KO
zebrafish model for chemical screening and identified novel 1,3,4-oxadiazol-2(3H)-one derivatives. Among them, compound 20e showed the most potent antiseizure efficacy in zebrafish behavioral
assays and significantly reduced locomotion-related seizure parameters
compared with repositioned drugs. In SCN1A+/– mice, 20e reduced seizure severity, delayed onset,
and suppressed hyperactivity. Notably, 20e normalized
pathological spike and burst activity in SMEI patient-derived iPSC
neurons. Mechanistically, 20e 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, compound 20e shows promise as a therapeutic agent for SMEI.