methyl 2-(4-(5,11-dihydro-2-ethyl-5-methyl-11-methylene-6-oxodibenz[b,e]azepin-8-yl)phenyl)acetate | 1395060-35-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: methyl 2-(4-(5,11-dihydro-2-ethyl-5-methyl-11-methylene-6-oxodibenz[b,e]azepin-8-yl)phenyl)acetate
• 英文别名: Methyl 2-[4-(2-ethyl-5-methyl-11-methylidene-6-oxobenzo[c][1]benzazepin-8-yl)phenyl]acetate；methyl 2-[4-(2-ethyl-5-methyl-11-methylidene-6-oxobenzo[c][1]benzazepin-8-yl)phenyl]acetate
• CAS: 1395060-35-1
• 化学式: C₂₇H₂₅NO₃
• 分子量: 411.5
• InChiKey: FSTMFLNRSDYTMU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 2-(4-(5,11-dihydro-2-ethyl-5-methyl-11-methylene-6-oxodibenz[b,e]azepin-8-yl)phenyl)acetate 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 3.0h， 生成 2-[4-(2-Ethyl-5-methyl-11-methylidene-6-oxobenzo[c][1]benzazepin-8-yl)phenyl]acetic acid
  参考文献：
  名称：

  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 Skeleton

  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 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.

  DOI：

  10.1021/jm3002394
• 作为产物：
  描述：

  2-溴-4-乙基苯胺 在 吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 potassium phosphate 、 四(三苯基膦)钯 、 (氯亚甲基)二甲基氯化铵 、 potassium acetate 、 sodium acetate 、 palladium diacetate 、 三溴化硼 、 sodium hydride 、 三苯基膦 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 44.0h， 生成 methyl 2-(4-(5,11-dihydro-2-ethyl-5-methyl-11-methylene-6-oxodibenz[b,e]azepin-8-yl)phenyl)acetate
  参考文献：
  名称：

  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 Skeleton

  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 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.

  DOI：

  10.1021/jm3002394

文献信息

• Design, Synthesis, and Biological Evaluation of Novel Transrepression-Selective Liver X Receptor (LXR) Ligands with 5,11-Dihydro-5-methyl-11-methylene-6<i>H</i>-dibenz[<i>b</i>,<i>e</i>]azepin-6-one Skeleton
  作者：Atsushi Aoyama、Kaori Endo-Umeda、Kenji Kishida、Kenji Ohgane、Tomomi Noguchi-Yachide、Hiroshi Aoyama、Minoru Ishikawa、Hiroyuki Miyachi、Makoto Makishima、Yuichi Hashimoto

  DOI：10.1021/jm3002394

  日期：2012.9.13

  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.