(R)-N-(4-chloro-3-(1-methyl-6-(trifluoromethoxy)-1H-benzo[d]-imidazol-2-yl)phenyl)-2-((5R,8S)-2,5-dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)propanamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (R)-N-(4-chloro-3-(1-methyl-6-(trifluoromethoxy)-1H-benzo[d]-imidazol-2-yl)phenyl)-2-((5R,8S)-2,5-dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)propanamide
• 英文别名: (2R)-N-[4-chloro-3-[1-methyl-6-(trifluoromethoxy)benzimidazol-2-yl]phenyl]-2-[(5R,8S)-2,5-dimethyl-5,6,7,8-tetrahydroquinolin-8-yl]propanamide
• 化学式: C₂₉H₂₈ClF₃N₄O₂
• 分子量: 557.015
• InChiKey: BGMHGWBNXBMNQS-CEQIKUNHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  69
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  青蒿素 在 lithium hydroxide monohydrate 、 硫酸 、 ammonium acetate 、 copper diacetate 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 18.33h， 生成 (R)-N-(4-chloro-3-(1-methyl-5-(trifluoromethoxy)-1H-benzo[d]-imidazol-2-yl)phenyl)-2-((5R,8S)-2,5-dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)propanamide 、 (R)-N-(4-chloro-3-(1-methyl-6-(trifluoromethoxy)-1H-benzo[d]-imidazol-2-yl)phenyl)-2-((5R,8S)-2,5-dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)propanamide
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists

  摘要：

  A series of novel Smo antagonists were developed either by directly incorporating the basic skeleton of the natural product artemisinin or by first breaking artemisinin into structurally simpler and stable intermediates and then reconstructing into diversified heterocyclic derivatives, equipped with a Smo-targeting bullet. 2-(2,5-Dimethy1-5,6,7,8-tetrahydroquinolin-8-yl)-N-arylpropanamide 65 was identified as the most potent, with an IC50 value of 9.53 nM against the Hh signaling pathway. Complementary mechanism studies confirmed that 65 inhibits Hh signaling pathway by targeting Smo and shares the same binding site as that of the tool drug cyclopamine. Meanwhile, 65 has a good plasma exposure and an acceptable oral bioavailability. Dose-dependent antiproliferative effects were observed in ptch+/;p53-/- medulloblastoma cells, and significant tumor growth inhibitions were achieved for 65 in the ptch+/-;p53-/- medulloblastoma allograft model.

  DOI：

  10.1021/acs.jmedchem.6b01247