Cholesterol 24-hydroxylase (CH24H, CYP46A1) is a brain-specific cytochrome P450 (CYP) family enzyme that plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24S-hydroxycholesterol (24HC). Despite its potential as a drug target, no potent and selective inhibitors for CH24H had been identified. In our research to discover novel CH24H inhibitors, a structure-based drug design (SBDD) using the X-ray co-crystal structure of a hit derivative was performed. A novel 4-arylpyridine core was initially designed as a key fragment to interact with CH24H, followed by the introduction of 4-benzyl-4-hydroxypiperidine led to generate a potent lead compound with four key specific interactions with CH24H. Further optimization led to identification of soticlestat (IC50 = 4.5 nM), a highly potent, selective, and brain-penetrant CH24H inhibitor. Oral administration of soticlestat to mice at 1, 3, 10 mg/kg resulted in a dose-dependent reduction of brain 24HC levels. Soticlestat is currently in Phase III clinical trials as a first-in-class ASM for the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The details of design, synthesis, and biological activities of soticlestat will constitute this presentation.

Discovery of soticlestat (TAK-935), a first-in-class antiseizure medication (ASM)

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