2. Academic Validation
  3. Development of Novel Small-Molecule Targeting SCN1A-Associated Severe Myoclonic Epilepsy of Infancy

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

  • J Med Chem. 2026 Feb 12;69(3):3362-3377. doi: 10.1021/acs.jmedchem.5c03293.
Dong Gun Kim 1,  Kyu-Seok Hwang 2,  Se Hwan Ahn 1,  Seong Soon Kim 2,  Yuji Son 2,  Sung Bum Park 2,  Won Hoon Jung 2,  Dae-Seop Shin 2,  Sung Hee Cho 2,  Byeong Wook Choi 1,  Pyeongkeun Kim 1,  Yerim Heo 1,  Minhee Kim 2,  Jung Yoon Yang 2,  Kyeong-Ryoon Lee 3 4,  Hyang-Ae Lee 5,  Jihun Kim 6,  Hoon-Chul Kang 6,  Ki Young Kim 2,  Myung Ae Bae 2 3,  Jin Hee Ahn 1 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 2 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 3 Department of Medical Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea.
  • 4 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 28116, Republic of Korea.
  • 5 Center for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea.
  • 6 Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Epilepsy Research Institute, Seoul 03722, Republic of Korea.
  • 7 JD Bioscience Inc, 208 Cheomdan-dwagiro, Buk-gu, Gwangju 61011, Republic of Korea.
PMID: 41574838 DOI: 10.1021/acs.jmedchem.5c03293
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.

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