肝X受体
化学
转换抑制
对接(动物)
立体化学
核受体
配体(生物化学)
受体
交易激励
生物化学
转录因子
基因
医学
护理部
作者
Atsushi Aoyama,Kaori Endo‐Umeda,Kenji Kishida,Kenji Ohgane,Tomomi Noguchi‐Yachide,Hiroshi Aoyama,Minoru Ishikawa,Hiroyuki Miyachi,Makoto Makishima,Yuichi Hashimoto
摘要
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 μM but showed no transactivational activity even at 30 μM. 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 LXRα. Next, further structural modification was performed with the guidance of docking simulations with LXRα, focusing on enhancing the binding of the ligands with LXRα 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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