Summary for 7N3M
| Entry DOI | 10.2210/pdb7n3m/pdb |
| Related | 7N3L |
| Descriptor | Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, N,N-dimethyl-1-[4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl]piperidine-4-carboxamide, ... (4 entities in total) |
| Functional Keywords | cyp46a1, ch24h, sbdd, drug discovery, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 55364.61 |
| Authors | |
| Primary citation | Kajita, Y.,Ikeda, S.,Yoshikawa, M.,Fukuda, H.,Watanabe, E.,Yano, J.,Lane, W.,Miyamoto, M.,Ishii, T.,Nishi, T.,Koike, T. Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors. J.Med.Chem., 65:3343-3358, 2022 Cited by PubMed Abstract: Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24-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 (soticlestat) and (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative (IC = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 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 at 30 mg/kg, indicating that is a promising tool for the novel and selective inhibition of CH24H. PubMed: 35166541DOI: 10.1021/acs.jmedchem.1c01898 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.698 Å) |
Structure validation
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