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

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Authors: Kim, Dong Gun ; Hwang, Kyu-Seok ; Ahn, Se Hwan ; Kim, Seong Soon ; Son, Yuji ; Park, Sung Bum ; Jung, Won Hoon ; Shin, Dae-Seop ; Cho, Sung Hee ; Choi, Byeong Wook ; Kim, Pyeongkeun ; Heo, Yerim ; Kim, Minhee ; Yang, Jung Yoon ; Lee, Kyeong-Ryoon ; Lee, Hyang-Ae ; Kim, Jihun ; Kang, Hoon-Chul ; Kim, Ki Young ; Bae, Myung Ae ; Ahn, Jin Hee

MeSH: Animals ; Anticonvulsants* / chemical synthesis ; Anticonvulsants* / chemistry ; Anticonvulsants* / pharmacokinetics ; Anticonvulsants* / pharmacology ; Anticonvulsants* / therapeutic use ; Disease Models, Animal ; Epilepsies, Myoclonic* / drug therapy ; Epilepsies, Myoclonic* / genetics ; Epilepsies, Myoclonic* / metabolism ; Humans ; Mice ; Mice, Knockout ; NAV1.1 Voltage-Gated Sodium Channel* / genetics ; NAV1.1 Voltage-Gated Sodium Channel* / metabolism ; Oxadiazoles* / chemistry ; Oxadiazoles* / pharmacology ; Oxadiazoles* / therapeutic use ; Small Molecule Libraries* / chemistry ; Small Molecule Libraries* / pharmacology ; Small Molecule Libraries* / therapeutic use ; Structure-Activity Relationship ; Zebrafish

Abstract: 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.