9NNI

Crystal structure of CYP46A1 with cyclopropyl[(4M)-4-(1,3-oxazol-5-yl)-6-(trifluoromethyl)-1H-indol-1-yl]methanone (compound 2b)

これはPDB形式変換不可エントリーです。

9NNI の概要

• エントリーDOI: 10.2210/pdb9nni/pdb
• 関連するPDBエントリー: 9NNA 9NNE
• 分子名称: Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, cyclopropyl[(4M)-4-(1,3-oxazol-5-yl)-6-(trifluoromethyl)-1H-indol-1-yl]methanone, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, ch24h, hydrolase-inhibitor complex, hydrolase/inhibitor
• 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: 55433.54

構造登録者

Yano, J.,Skene, R.J. (登録日: 2025-03-05, 公開日: 2025-07-02)

主引用文献

Ito, Y.,Hasui, T.,Kimura, E.,Nomura, I.,Fukuda, H.,Ando, H.K.,Watanabe, E.,Yano, J.,Skene, R.,Miyamoto, M.,Ishii, T.,Nishi, T.,Koike, T.
Structure-based design of a novel series of cholesterol 24-hydroxylase (CH24H) inhibitors bearing 1,3-oxazole as a heme-iron binding group.
Bioorg.Med.Chem., 128:118280-118280, 2025

PubMed Abstract: Herein, we describe the design, synthesis, and pharmacological evaluation of novel 1,3-oxazole-based inhibitors of cholesterol 24-hydroxylase (CH24H; CYP46A1), a brain-specific cytochrome P450 (CYP) enzyme that metabolizes cholesterol to 24Shydroxycholesterol (24HC). Starting with compound 1a, a scaffold-hopping approach using structure-based drug design identified a series of imidazo[1,2-a]pyridine-3- carboxamide derivatives as novel CH24H inhibitors. Subsequent optimization guided by ligand-lipophilicity efficiency metrics resulted in the discovery of 3k (IC = 4.5 nM) with potent and selective CH24H inhibition. Oral administration of compound 3k at 10 mg/kg resulted in brain penetration and 24HC reduction in the mouse brain. These results suggest that 1,3-oxazole is a promising heme-iron binder which can provide potent and selective inhibitors against CYP enzymes, including CH24H.

PubMed: 40541064
DOI: 10.1016/j.bmc.2025.118280

実験手法

X-RAY DIFFRACTION (1.7 Å)