期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 17, 页码 7360-7377出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3002394
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [21790107, 22249006] Funding Source: KAKEN
To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity of the 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and transactivational activity. Structural modification of 10 based on the reported X-ray crystal structure of the LXR ligand-binding domain led to a series of compounds, of which almost all exhibited transrepressional activity at 1 or 10 mu M but showed no transactivational activity even at 30 mu M. Among the compounds obtained, 18 and 22 were confirmed to have LXR-dependent transrepressional activity by using peritoneal macrophages from wild-type and LXR-null mice. A newly developed fluorescence polarization assay indicated that they bind directly to LXR alpha. Next, further structural modification was performed with the guidance of docking simulations with LXR alpha, focusing on enhancing the binding of the ligands with LXR alpha through the introduction of substituents or heteroatom(s). Among the compounds synthesized, compound 48, bearing a hydroxyl group, showed potent, selective, and dose-dependent transrepressional activity.
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