Download MendeleyDiscovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.
Kajita, Y., Ikeda, S., Yoshikawa, M., Fukuda, H., Watanabe, E., Yano, J., Lane, W., Miyamoto, M., Ishii, T., Nishi, T., Koike, T.(2022) J Med Chem 65: 3343-3358
- PubMed: 35166541
- DOI: https://doi.org/10.1021/acs.jmedchem.1c01898
- Primary Citation of Related Structures:
7N3L, 7N3M - PubMed Abstract:
Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24 S -hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds 1 (soticlestat) and 2 (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 17 (IC 50 = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 17 revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of 17 at 30 mg/kg, indicating that 17 is a promising tool for the novel and selective inhibition of CH24H.
Organizational Affiliation:
Research, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
