TY - JOUR
T1 - Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)
AU - Koike, Tatsuki
AU - Yoshikawa, Masato
AU - Ando, Haruhi Kamisaki
AU - Farnaby, William
AU - Nishi, Toshiya
AU - Watanabe, Etsurou
AU - Yano, Jason
AU - Miyamoto, Maki
AU - Kondo, Shigeru
AU - Ishii, Tsuyoshi
AU - Kuroita, Takanobu
N1 - Funding Information:
GM/CA@APS has been funded by the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006, P30GM138396). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The Berkeley Center for Structural Biology is supported in part by the Howard Hughes Medical Institute. The Advanced Light Source is a Department of Energy Office of Science User Facility under Contract No. DE-AC02-05CH11231.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society. CC-BY.
PY - 2021/8/26
Y1 - 2021/8/26
N2 - 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 24S-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, IC50 = 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.
AB - 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 24S-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, IC50 = 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.
KW - Alkyls
KW - Bioinorganic chemistry
KW - Central nervous system
KW - Inhibition
KW - Molecular mechanics
UR - http://www.scopus.com/inward/record.url?scp=85113878738&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00864
DO - 10.1021/acs.jmedchem.1c00864
M3 - Article
C2 - 34387987
AN - SCOPUS:85113878738
SN - 0022-2623
VL - 64
SP - 12228
EP - 12244
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -