Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)

Tatsuki Koike; Masato Yoshikawa; Haruhi Kamisaki Ando; William Farnaby; Toshiya Nishi; Etsurou Watanabe; Jason Yano; Maki Miyamoto; Shigeru Kondo; Tsuyoshi Ishii; Takanobu Kuroita

doi:10.1021/acs.jmedchem.1c00864

Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)

Tatsuki Koike (Lead / Corresponding author), Masato Yoshikawa, Haruhi Kamisaki Ando, William Farnaby, Toshiya Nishi, Etsurou Watanabe, Jason Yano, Maki Miyamoto, Shigeru Kondo, Tsuyoshi Ishii, Takanobu Kuroita

Biological Chemistry and Drug Discovery

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14 Citations (Scopus)

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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 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.

Original language	English
Pages (from-to)	12228-12244
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	16
Early online date	13 Aug 2021
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00864
Publication status	Published - 26 Aug 2021

Keywords

Alkyls
Bioinorganic chemistry
Central nervous system
Inhibition
Molecular mechanics

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c00864Licence: CC BY

Final Published VersionFinal published version, 4.31 MBLicence: CC BY

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title = "Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)",

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 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.",

keywords = "Alkyls, Bioinorganic chemistry, Central nervous system, Inhibition, Molecular mechanics",

author = "Tatsuki Koike and Masato Yoshikawa and Ando, {Haruhi Kamisaki} and William Farnaby and Toshiya Nishi and Etsurou Watanabe and Jason Yano and Maki Miyamoto and Shigeru Kondo and Tsuyoshi Ishii and Takanobu Kuroita",

note = "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: {\textcopyright} 2021 The Authors. Published by American Chemical Society. CC-BY.",

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doi = "10.1021/acs.jmedchem.1c00864",

language = "English",

volume = "64",

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journal = "Journal of Medicinal Chemistry",

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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

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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 -

Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)

Abstract

Keywords

ASJC Scopus subject areas

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Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

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