Download MendeleyDesign and identification of brain-penetrant, potent, and selective 1,3-oxazole-based cholesterol 24-hydroxylase (CH24H) inhibitors.
Ito, Y., Kimura, E., Nomura, I., Watanabe, E., Yano, J., Skene, R., Miyamoto, M., Ishii, T., Nishi, T., Koike, T.(2025) Bioorg Med Chem 124: 118182-118182
- PubMed: 40215592
- DOI: https://doi.org/10.1016/j.bmc.2025.118182
- Primary Citation of Related Structures:
9NNJ, 9NNM, 9NNO - 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.
Organizational Affiliation:
Research, Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa 251-8555, Japan.
