Indole deriv. 15

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: Indole deriv. 15
• 英文别名: 6-methoxy-N-(1-methylindol-4-yl)-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
• 化学式: C₂₅H₂₉N₅O₃
• 分子量: 447.537
• InChiKey: PIDIUJOXHKWXAQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  73.7
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-(3-羟丙基)吗啉 在 盐酸 、 氯化亚砜 、 氨 、 N,N-二甲基甲酰胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 甲醇 、 二氯甲烷 、 异丙醇 为溶剂， 反应 4.5h， 生成 Indole deriv. 15
  参考文献：
  名称：

  Discovery of a New Class of Anilinoquinazoline Inhibitors with High Affinity and Specificity for the Tyrosine Kinase Domain of c-Src

  摘要：

  Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.

  DOI：

  10.1021/jm030317k

文献信息

• Discovery of a New Class of Anilinoquinazoline Inhibitors with High Affinity and Specificity for the Tyrosine Kinase Domain of c-Src
  作者：Patrick A. Plé、Tim P. Green、Laurent F. Hennequin、Jon Curwen、Michael Fennell、Jack Allen、Christine Lambert-van der Brempt、Gerard Costello

  DOI：10.1021/jm030317k

  日期：2004.2.1

  Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.