7LS3

Co-complex CYP46A1 with 8114 (3f)

Summary for 7LS3

• Entry DOI: 10.2210/pdb7ls3/pdb
• Related: 7LRL
• Descriptor: Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, (5-methyl-2-pyridin-4-yl-phenyl)-[4-oxidanyl-4-(phenylmethyl)piperidin-1-yl]methanone, ... (4 entities in total)
• Functional Keywords: cyp46a1, ch24h, sbdd, drug discovery, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 55437.70

Authors

Lane, W.,Yano, J. (deposition date: 2021-02-17, release date: 2021-08-25, Last modification date: 2023-10-18)

Primary citation

Koike, T.,Yoshikawa, M.,Ando, H.K.,Farnaby, W.,Nishi, T.,Watanabe, E.,Yano, J.,Miyamoto, M.,Kondo, S.,Ishii, T.,Kuroita, T.
Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H).
J.Med.Chem., 64:12228-12244, 2021

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-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 . Optimization of 4-arylpyridine derivatives led us to identify ((4-benzyl-4-hydroxypiperidin-1-yl)(2,4'-bipyridin-3-yl)methanone, IC = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound (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.

PubMed: 34387987
DOI: 10.1021/acs.jmedchem.1c00864

Experimental method

X-RAY DIFFRACTION (2.15 Å)