Download MendeleyDiscovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H).
Koike, T., Yoshikawa, M., Ando, H.K., Farnaby, W., Nishi, T., Watanabe, E., Yano, J., Miyamoto, M., Kondo, S., Ishii, T., Kuroita, T.(2021) J Med Chem 64: 12228-12244
- PubMed: 34387987
- DOI: https://doi.org/10.1021/acs.jmedchem.1c00864
- Primary Citation of Related Structures:
7LRL, 7LS3, 7LS4 - PubMed Abstract:
Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24 S -hydroxycholesterol (24HC). Despite a wide range of potential of CH24H as a drug target, no potent and selective inhibitors have been identified. Here, we report on the structure-based drug design (SBDD) of novel 4-arylpyridine derivatives based on the X-ray co-crystal structure of hit derivative 1b . Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1-yl)(2,4'-bipyridin-3-yl)methanone, IC 50 = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound 3v (soticlestat, also known as TAK-935) is currently under clinical investigation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel drug class for epilepsies.
Organizational Affiliation:
Research, Takeda Pharmaceutical Company Ltd., 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
