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

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)
52 Downloads (Pure)

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 languageEnglish
Pages (from-to)12228-12244
Number of pages17
JournalJournal of Medicinal Chemistry
Volume64
Issue number16
Early online date13 Aug 2021
DOIs
Publication statusPublished - 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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