1-[2-fluoro-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-phenyl]-3-(2-methylpyridin-4-yl)urea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1-[2-fluoro-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-phenyl]-3-(2-methylpyridin-4-yl)urea
• 英文别名: 1-[2-fluoro-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]-3-(2-methylpyridin-4-yl)urea
• 化学式: C₂₀H₁₇FN₆O
• 分子量: 376.393
• InChiKey: AWSGOVJNEZMVLZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  95.6
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-甲基-4-氨基吡啶 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 6.0h， 生成 1-[2-fluoro-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-phenyl]-3-(2-methylpyridin-4-yl)urea
  参考文献：
  名称：

  Discovery of bis-aryl urea derivatives as potent and selective Limk inhibitors: Exploring Limk1 activity and Limk1/ROCK2 selectivity through a combined computational study

  摘要：

  Lim kinase (Limk), a proline/serine-rich sequence, can regulate the polymerization of the actin filaments by phosphorylating, and it is found to be highly involved in various human diseases. In this paper, 47 reported Limk1 inhibitors with bis-aryl urea scaffold were used to design potent and selective Limk inhibitors by computational approaches. Firstly, the structure-Limk1 activity relationship models (3D-QSAR) and structure-Limk1/ROCK2 selectivity relationship models (3D-QSSR) were developed and both 3D-QSAR and 3D-QSSR models showed good correlative and predictive abilities. Then, the molecular docking and molecular dynamics (MD) simulations were employed to validate the optimal docking conformation and explore the binding affinities. Finally, five new compounds were designed and all of them exhibited good Limk1 inhibition and Limk1/ROCK2 selectivity after synthesis and biological evaluation, which demonstrated that the obtained information from computational studies were valuable to guide Limk inhibitors' design. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.10.041

文献信息

• Discovery of bis-aryl urea derivatives as potent and selective Limk inhibitors: Exploring Limk1 activity and Limk1/ROCK2 selectivity through a combined computational study
  作者：Jiaxin Cui、Mei Ding、Wei Deng、Yan Yin、Zhonghua Wang、Hong Zhou、Guofeng Sun、Yu Jiang、Yangbo Feng

  DOI：10.1016/j.bmc.2015.10.041

  日期：2015.12

  Lim kinase (Limk), a proline/serine-rich sequence, can regulate the polymerization of the actin filaments by phosphorylating, and it is found to be highly involved in various human diseases. In this paper, 47 reported Limk1 inhibitors with bis-aryl urea scaffold were used to design potent and selective Limk inhibitors by computational approaches. Firstly, the structure-Limk1 activity relationship models (3D-QSAR) and structure-Limk1/ROCK2 selectivity relationship models (3D-QSSR) were developed and both 3D-QSAR and 3D-QSSR models showed good correlative and predictive abilities. Then, the molecular docking and molecular dynamics (MD) simulations were employed to validate the optimal docking conformation and explore the binding affinities. Finally, five new compounds were designed and all of them exhibited good Limk1 inhibition and Limk1/ROCK2 selectivity after synthesis and biological evaluation, which demonstrated that the obtained information from computational studies were valuable to guide Limk inhibitors' design. (C) 2015 Elsevier Ltd. All rights reserved.