Download MendeleyStructure-based design of a novel series of cholesterol 24-hydroxylase (CH24H) inhibitors bearing 1,3-oxazole as a heme-iron binding group.
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.(2025) Bioorg Med Chem 128: 118280-118280
- PubMed: 40541064
- DOI: https://doi.org/10.1016/j.bmc.2025.118280
- Primary Citation of Related Structures:
9NNA, 9NNE, 9NNI - 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 50 = 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.
Organizational Affiliation:
Research, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
