9NNE
Crystal structure of CYP46A1 with (morpholin-4-yl)[(4R,8M)-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanone (compound 2h)
This is a non-PDB format compatible entry.
Summary for 9NNE
| Entry DOI | 10.2210/pdb9nne/pdb |
| Related | 9NNA |
| Descriptor | Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, (morpholin-4-yl)[(4R,8M)-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanone, ... (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 | 55417.50 |
| Authors | |
| Primary citation | 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 Cited by 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: 40541064DOI: 10.1016/j.bmc.2025.118280 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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