(Z)-3-((4-(2-(diethylamino)ethylcarbamoyl)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylic acid ethylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (Z)-3-((4-(2-(diethylamino)ethylcarbamoyl)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylic acid ethylamide
• 英文别名: 3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone；(3Z)-3-[[4-[2-(diethylamino)ethylcarbamoyl]anilino]-phenylmethylidene]-N-ethyl-2-oxo-1H-indole-6-carboxamide
• 化学式: C₃₁H₃₅N₅O₃
• 分子量: 525.651
• InChiKey: AOWURAHNMNLYFX-DQSJHHFOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.44
• 重原子数：
  39.0
• 可旋转键数：
  11.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  102.57
• 氢给体数：
  4.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  (Z)-N-ethyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxamide 、 普鲁卡因胺 在 trimethylsilylimidazole 作用下， 以 四氢呋喃 为溶剂， 反应 0.25h， 以88%的产率得到(Z)-3-((4-(2-(diethylamino)ethylcarbamoyl)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylic acid ethylamide
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor β Receptor I (TGFβRI)

  摘要：

  Inhibition of transforming growth factor β (TGFβ) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. Indolinones substituted in position 6 were identified as a new chemotype inhibiting TGFβRI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRα), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGFβRI inhibitors, was not targeted by derivatives based on the indolinone chemotype. Guided by an X-ray structure of lead compound 5 (BIBF0775) soaked into the kinase domain of TGFβRI, optimization furnished potent and selective inhibitors of TGFβRI. Potent inhibition translated well into good inhibition of TGFβRI-mediated phosphorylation of Smad2/3, demonstrating efficacy in a cellular setting. Optimized compounds were extensively profiled on a 232-kinase panel and showed low cross-reactivities within the human kinome.

  DOI：

  10.1021/jm100812a

文献信息

• Design, Synthesis, and Evaluation of Indolinones as Inhibitors of the Transforming Growth Factor β Receptor I (TGFβRI)
  作者：Gerald J. Roth、Armin Heckel、Trixi Brandl、Matthias Grauert、Stefan Hoerer、Joerg T. Kley、Gisela Schnapp、Patrick Baum、Detlev Mennerich、Andreas Schnapp、John E. Park

  DOI：10.1021/jm100812a

  日期：2010.10.28

  Inhibition of transforming growth factor β (TGFβ) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. Indolinones substituted in position 6 were identified as a new chemotype inhibiting TGFβRI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRα), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGFβRI inhibitors, was not targeted by derivatives based on the indolinone chemotype. Guided by an X-ray structure of lead compound 5 (BIBF0775) soaked into the kinase domain of TGFβRI, optimization furnished potent and selective inhibitors of TGFβRI. Potent inhibition translated well into good inhibition of TGFβRI-mediated phosphorylation of Smad2/3, demonstrating efficacy in a cellular setting. Optimized compounds were extensively profiled on a 232-kinase panel and showed low cross-reactivities within the human kinome.