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

## TL;DR

Researchers developed a new drug candidate, compound 20e, that shows strong antiseizure effects in a rare and severe childhood epilepsy caused by SCN1A mutations.

## Contribution

A novel small-molecule, compound 20e, was identified and shown to effectively reduce seizures in multiple models of SMEI.

## Key findings

- Compound 20e reduced seizure severity and delayed onset in SCN1A+/– mice.
- It normalized abnormal brain activity in patient-derived neurons and improved behavioral seizure parameters in zebrafish.
- Compound 20e showed favorable safety and pharmacokinetic profiles, including good blood-brain barrier penetration.

## 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.