6-chloro-N-methyl-N-(4-(trifluoromethoxy)phenyl)-pyrimidin-4-amine | 959573-80-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 6-chloro-N-methyl-N-(4-(trifluoromethoxy)phenyl)-pyrimidin-4-amine
• 英文别名: (6-Chloro-pyrimidin-4-yl)-methyl-(4-trifluoromethoxy-phenyl)-amine；6-chloro-N-methyl-N-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine
• CAS: 959573-80-9
• 化学式: C₁₂H₉ClF₃N₃O
• 分子量: 303.671
• InChiKey: JWYNWYRHZUXMIC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  38.2
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-chloro-N-methyl-N-(4-(trifluoromethoxy)phenyl)-pyrimidin-4-amine 、 3-氨基甲酰基苯硼酸 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 水 、 乙腈 为溶剂， 反应 7.0h， 以59%的产率得到3-(6-(methyl(4-(trifluoromethoxy)phenyl)amino)-pyrimidin-4-yl)benzamide
  参考文献：
  名称：

  Direct Binding Assay for the Detection of Type IV Allosteric Inhibitors of Abl

  摘要：

  Abelson (Abl) tyrosine kinase is an important cellular enzyme that is rendered constitutively active in the breakpoint cluster region (BCR)-Abl fusion protein, contributing to several forms of leukemia. Although inhibiting BCR-Abl activity with imatinib shows great clinical success, many patients acquire secondary mutations that result in resistance to imatinib. Second-generation inhibitors such as dasatinib and nilotinib can overcome the majority of these mutations but fail to treat patients with an especially prevalent T315I mutation at the gatekeeper position of the kinase domain. However, a combination of nilotinib with an allosteric type IV inhibitor was recently shown to overcome this clinically relevant point mutation. In this study, we present the development of a direct binding assay that enables the straightforward detection of allosteric inhibitors which bind within the myristate pocket of Abl. The assay is amenable to high-throughput screening and exclusively detects the binding of ligands to this unique allosteric site.

  DOI：

  10.1021/ja303858w
• 作为产物：
  描述：

  对三氟甲氧基苯胺 在 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.33h， 生成 6-chloro-N-methyl-N-(4-(trifluoromethoxy)phenyl)-pyrimidin-4-amine
  参考文献：
  名称：

  Direct Binding Assay for the Detection of Type IV Allosteric Inhibitors of Abl

  摘要：

  Abelson (Abl) tyrosine kinase is an important cellular enzyme that is rendered constitutively active in the breakpoint cluster region (BCR)-Abl fusion protein, contributing to several forms of leukemia. Although inhibiting BCR-Abl activity with imatinib shows great clinical success, many patients acquire secondary mutations that result in resistance to imatinib. Second-generation inhibitors such as dasatinib and nilotinib can overcome the majority of these mutations but fail to treat patients with an especially prevalent T315I mutation at the gatekeeper position of the kinase domain. However, a combination of nilotinib with an allosteric type IV inhibitor was recently shown to overcome this clinically relevant point mutation. In this study, we present the development of a direct binding assay that enables the straightforward detection of allosteric inhibitors which bind within the myristate pocket of Abl. The assay is amenable to high-throughput screening and exclusively detects the binding of ligands to this unique allosteric site.

  DOI：

  10.1021/ja303858w

文献信息

• Expanding the Diversity of Allosteric Bcr-Abl Inhibitors
  作者：Xianming Deng、Barun Okram、Qiang Ding、Jianming Zhang、Yongmun Choi、Francisco J. Adrián、Amy Wojciechowski、Guobao Zhang、Jianwei Che、Badry Bursulaya、Sandra W. Cowan-Jacob、Gabriele Rummel、Taebo Sim、Nathanael S. Gray

  DOI：10.1021/jm100555f

  日期：2010.10.14

  Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure−activity

  伊马替尼对 Bcr-Abl 激酶活性的抑制用于治疗慢性粒细胞白血病 (CML)，目前作为用小分子靶向显性癌基因的范例。我们最近报道了 GNF-2 ( 1 ) 和 GNF-5 ( 2 ) 作为靶向肉豆蔻酸结合位点的细胞 Bcr-Abl 激酶活性的选择性非 ATP 竞争性抑制剂的发现。在这里，我们使用基于细胞的结构-活性关系来指导能够与肉豆蔻酸酯结合位点结合的配体的优化和多样化，并使基于 Abl-化合物1的发现合理化共晶。我们阐明了获得针对 Bcr-Abl 转化细胞的强效抗增殖活性所需的结构-活性关系，并报告了新化合物（5g、5h、6a、14d和21j-I）的发现，这些化合物显示出改进的效力或药理特性。这项工作表明，多种结构可以有效地靶向 Bcr-Abl 肉豆蔻酸酯结合位点，并为开发可靶向该结合位点的药物提供了新的线索。
• Direct Binding Assay for the Detection of Type IV Allosteric Inhibitors of Abl
  作者：Ralf Schneider、Christian Becker、Jeffrey R. Simard、Matthäus Getlik、Nina Bohlke、Petra Janning、Daniel Rauh

  DOI：10.1021/ja303858w

  日期：2012.6.6

  Abelson (Abl) tyrosine kinase is an important cellular enzyme that is rendered constitutively active in the breakpoint cluster region (BCR)-Abl fusion protein, contributing to several forms of leukemia. Although inhibiting BCR-Abl activity with imatinib shows great clinical success, many patients acquire secondary mutations that result in resistance to imatinib. Second-generation inhibitors such as dasatinib and nilotinib can overcome the majority of these mutations but fail to treat patients with an especially prevalent T315I mutation at the gatekeeper position of the kinase domain. However, a combination of nilotinib with an allosteric type IV inhibitor was recently shown to overcome this clinically relevant point mutation. In this study, we present the development of a direct binding assay that enables the straightforward detection of allosteric inhibitors which bind within the myristate pocket of Abl. The assay is amenable to high-throughput screening and exclusively detects the binding of ligands to this unique allosteric site.