Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24S-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. Recently, a selective CH24H inhibitor, soticlestat (TAK-935), demonstrated in mice the therapeutic potential of CH24H inhibition as an antiseizure medication. To further validate the therapeutic potential of CH24H inhibition, we designed and synthesized a novel series of CH24H inhibitors through a structure-based drug design (SBDD) approach starting from soticlestat and thioperamide. Optimization focusing on ligand-lipophilicity efficiency value resulted in the improvement of CYP selectivity leading to the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 1 (IC50 = 8.5 nM). Oral administration of 1 (30 mg/kg, p.o.) significantly reduced 24HC levels by 26% in the mouse brain, indicating that 1 is the promising tool for a selective inhibition of CH24H. In this presentation, the binding mode difference among known CH24H inhibitors is also discussed based on the X-ray crystal structure of CH24H in complex with compound 1.

Discovery of highly potent and selective cholesterol 24-hydroxylase (CH24H) inhibitors with a novel binding mode

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