3-(3,4,5-trimethoxyphenyl)-1H-indazole-5-carbaldehyde | 1307896-63-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(3,4,5-trimethoxyphenyl)-1H-indazole-5-carbaldehyde
• CAS: 1307896-63-4
• 化学式: C₁₇H₁₆N₂O₄
• 分子量: 312.325
• InChiKey: GSIXQXIKVFPTMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  73.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(3,4,5-trimethoxyphenyl)-1H-indazole-5-carbaldehyde 、 1H-1,2,4-三唑-1-乙腈 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以17%的产率得到(E)-2-(1H-1,2,4-triazol-1-yl)-3-(3-(3,4,5-trimethoxyphenyl)-1H-indazol-5-yl)acrylonitrile
  参考文献：
  名称：

  以动力学和计算分析为指导的可逆、半胱氨酸靶向迈克尔受体的设计

  摘要：

  共价修饰半胱氨酸硫醇的亲电探针通常表现出增强的药理学效力和选择性。尽管已经报道了可逆迈克尔受体，但对可逆性的结构要求知之甚少。在这里，我们报告了一类新的基于丙烯腈的迈克尔受体，由芳基或杂芳基吸电子基团激活。我们证明这些丙烯腈的硫醇加合物以超过 3 个数量级的速率进行 β-消除。这些速率与计算出的相应碳负离子的质子亲和力成反比，从而能够以可预测的方式调整硫醇-迈克尔反应的内在可逆性。我们将这些原理应用于设计具有改进特性的新型可逆共价激酶抑制剂。一种此类抑制剂的共晶结构揭示了 1,2,4-三唑激活基团与激酶之间的特定非共价相互作用。我们的实验和计算研究能够设计新的迈克尔受体，扩展可逆的、半胱氨酸靶向的亲电子试剂的调色板。

  DOI：

  10.1021/ja505194w
• 作为产物：
  描述：

  1H-吲唑-5-甲醛 在 四(三苯基膦)钯 、 碘 、 potassium carbonate 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.5h， 生成 3-(3,4,5-trimethoxyphenyl)-1H-indazole-5-carbaldehyde
  参考文献：
  名称：

  Electrophilic Fragment-Based Design of Reversible Covalent Kinase Inhibitors

  摘要：

  Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.

  DOI：

  10.1021/ja401221b

文献信息

• KINASE INHIBITORS
  申请人：Taunton, JR. John William

  公开号：US20130035325A1

  公开（公告）日：2013-02-07

  Methods of inhibiting kinases using kinase inhibitors having olefin moieties are disclosed.

  使用具有烯烃基团的激酶抑制剂抑制激酶的方法被披露。
• US9505766B2
  申请人：——

  公开号：US9505766B2

  公开（公告）日：2016-11-29
• [EN] KINASE INHIBITORS<br/>[FR] INHIBITEURS DE KINASES
  申请人：UNIV CALIFORNIA

  公开号：WO2011060440A2

  公开（公告）日：2011-05-19

  Methods of inhibiting kinases using kinase inhibitors having olefin moieties are disclosed.
• Electrophilic Fragment-Based Design of Reversible Covalent Kinase Inhibitors
  作者：Rand M. Miller、Ville O. Paavilainen、Shyam Krishnan、Iana M. Serafimova、Jack Taunton

  DOI：10.1021/ja401221b

  日期：2013.4.10

  Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.
• Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis
  作者：Shyam Krishnan、Rand M. Miller、Boxue Tian、R. Dyche Mullins、Matthew P. Jacobson、Jack Taunton

  DOI：10.1021/ja505194w

  日期：2014.9.10

  that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-based Michael acceptors, activated by aryl or heteroaryl electron-withdrawing groups. We demonstrate that thiol adducts of these acrylonitriles

  共价修饰半胱氨酸硫醇的亲电探针通常表现出增强的药理学效力和选择性。尽管已经报道了可逆迈克尔受体，但对可逆性的结构要求知之甚少。在这里，我们报告了一类新的基于丙烯腈的迈克尔受体，由芳基或杂芳基吸电子基团激活。我们证明这些丙烯腈的硫醇加合物以超过 3 个数量级的速率进行 β-消除。这些速率与计算出的相应碳负离子的质子亲和力成反比，从而能够以可预测的方式调整硫醇-迈克尔反应的内在可逆性。我们将这些原理应用于设计具有改进特性的新型可逆共价激酶抑制剂。一种此类抑制剂的共晶结构揭示了 1,2,4-三唑激活基团与激酶之间的特定非共价相互作用。我们的实验和计算研究能够设计新的迈克尔受体，扩展可逆的、半胱氨酸靶向的亲电子试剂的调色板。