9NNM

Crystal structure of CYP46A1 with 3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)-5-(trifluoromethyl)phenyl]benzamide (compound 3f)

This is a non-PDB format compatible entry.

Summary for 9NNM

• Entry DOI: 10.2210/pdb9nnm/pdb
• Related: 9NNJ
• Descriptor: Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, 3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)-5-(trifluoromethyl)phenyl]benzamide, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, ch24h, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 55417.93

Authors

Yano, J.,Skene, R.J. (deposition date: 2025-03-05, release date: 2025-04-23)

Primary citation

Ito, Y.,Kimura, E.,Nomura, I.,Watanabe, E.,Yano, J.,Skene, R.,Miyamoto, M.,Ishii, T.,Nishi, T.,Koike, T.
Design and identification of brain-penetrant, potent, and selective 1,3-oxazole-based cholesterol 24-hydroxylase (CH24H) inhibitors.
Bioorg.Med.Chem., 124:118182-118182, 2025

PubMed Abstract: Azole-, pyridine-, and pyrimidine-based cytochrome P450 (CYP) inhibitors strongly bind to CYP enzymes through the coordination between the heme iron of CYP and the sp2-nitrogen atoms of heteroaromatic rings, providing potent pharmacological effects by inhibiting the initiation of the catalytic cycles of target CYP enzymes. Although imidazole-, 1,2,4-triazole-, pyridine-, and pyrimidine-based CYP inhibitors have been widely explored, 1,3-oxazole-based CYP inhibitors have received little attention. In this study, we designed and identified novel 1,3-oxazole-based inhibitors of cholesterol 24- hydroxylase (CH24H; CYP46A1), a brain-specific enzyme involved in cholesterol catabolism, to form 24S-hydroxycholesterol. Detailed insights into the CH24H-ligand interactions were provided by the crystal structures of 1,3-oxazole compounds, including high-throughput screening hit 2 and rationally designed inhibitor 3f. Optimization of 3f led to the identification of 1,3-oxazole derivative 4 l as a potent, selective, and brain-penetrable CH24H inhibitor that significantly reduced 24HC levels in the mouse brain. The design of 1,3-oxazole-based CYP inhibitors holds the potential for the discovery of novel inhibitors with significant potency against a broad spectrum of CYP enzymes.

PubMed: 40215592
DOI: 10.1016/j.bmc.2025.118182

Experimental method

X-RAY DIFFRACTION (1.7 Å)