7N3M

Co-complex CYP46A1 with 0431 (compound 17)

これはPDB形式変換不可エントリーです。

7N3M の概要

• エントリーDOI: 10.2210/pdb7n3m/pdb
• 関連するPDBエントリー: 7N3L
• 分子名称: Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, N,N-dimethyl-1-[4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl]piperidine-4-carboxamide, ... (4 entities in total)
• 機能のキーワード: cyp46a1, ch24h, sbdd, drug discovery, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55364.61

構造登録者

Lane, W.,Yano, J. (登録日: 2021-06-01, 公開日: 2022-02-23, 最終更新日: 2023-10-18)

主引用文献

Kajita, Y.,Ikeda, S.,Yoshikawa, M.,Fukuda, H.,Watanabe, E.,Yano, J.,Lane, W.,Miyamoto, M.,Ishii, T.,Nishi, T.,Koike, T.
Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.
J.Med.Chem., 65:3343-3358, 2022

PubMed Abstract: Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds (soticlestat) and (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative (IC = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of at 30 mg/kg, indicating that is a promising tool for the novel and selective inhibition of CH24H.

PubMed: 35166541
DOI: 10.1021/acs.jmedchem.1c01898

実験手法

X-RAY DIFFRACTION (1.698 Å)