2-[4-(3-methoxyphenoxy)phenyl]-1H-benzimidazole-5-carboxylic acid amide | 1028903-37-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-[4-(3-methoxyphenoxy)phenyl]-1H-benzimidazole-5-carboxylic acid amide
• 英文别名: 2-(4-(3-methoxyphenoxy)phenyl)-1H-benzo[d]imidazole-5-carboxamide
• CAS: 1028903-37-8
• 化学式: C₂₁H₁₇N₃O₃
• 分子量: 359.384
• InChiKey: YUERLIQZCIZWCN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.13
• 重原子数：
  27.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  90.23
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-[4-(3-methoxyphenoxy)phenyl]-1H-benzimidazole-5-carboxylic acid amide 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 以93%的产率得到2-[4-(3-Hydroxy-phenoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide
  参考文献：
  名称：

  Checkpoint Kinase Inhibitors:  SAR and Radioprotective Properties of a Series of 2-Arylbenzimidazoles

  摘要：

  The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. High-throughput screening of purified human chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC50 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependently protects human CD4+ and CD8+ T-cells from apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of chk2 could be a useful adjuvant to radiotherapy, increasing the therapeutic window of such treatment.

  DOI：

  10.1021/jm0495935
• 作为产物：
  描述：

  3,4-二氨基苯甲酸 在 sodium metabisulfite 、 N,N'-羰基二咪唑 作用下， 以 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 2-[4-(3-methoxyphenoxy)phenyl]-1H-benzimidazole-5-carboxylic acid amide
  参考文献：
  名称：

  Checkpoint Kinase Inhibitors:  SAR and Radioprotective Properties of a Series of 2-Arylbenzimidazoles

  摘要：

  The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. High-throughput screening of purified human chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC50 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependently protects human CD4+ and CD8+ T-cells from apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of chk2 could be a useful adjuvant to radiotherapy, increasing the therapeutic window of such treatment.

  DOI：

  10.1021/jm0495935

文献信息

• Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography
  作者：Cornelis Matijssen、M. Cris Silva-Santisteban、Isaac M. Westwood、Samerene Siddique、Vanessa Choi、Peter Sheldrake、Rob L.M. van Montfort、Julian Blagg

  DOI：10.1016/j.bmc.2012.09.024

  日期：2012.11

  Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature.