Design, Synthesis, and Biological Evaluation of Novel Transrepression-Selective Liver X Receptor (LXR) Ligands with 5,11-Dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one S

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• 作者：Atsushi Aoyama ; Kaori Endo-Umeda ; Kenji Kishida ; Kenji Ohgane ; Tomomi Noguchi-Yachide ; Hiroshi Aoyama ; Minoru Ishikawa ; Hiroyuki Miyachi ; Makoto Makishima ; Yuichi Hashimoto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7360-7377
• 全文大小：735K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

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 渭M but showed no transactivational activity even at 30 渭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伪. Next, further structural modification was performed with the guidance of docking simulations with LXR伪, focusing on enhancing the binding of the ligands with LXR伪 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.