3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide | 1286238-51-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
• 英文别名: VE-821；3-amino-N-phenyl-6-(4-propan-2-ylsulfonylphenyl)pyrazine-2-carboxamide
• CAS: 1286238-51-4
• 化学式: C₂₀H₂₀N₄O₃S
• 分子量: 396.47
• InChiKey: SIJVOCXXIKNHDX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-氨基吡嗪-2-羧酸甲酯 在 4-二甲氨基吡啶 、 N-溴代丁二酰亚胺(NBS) 、 sodium carbonate 、 N,N-二异丙基乙胺 、 N,N'-羰基二咪唑 、 lithium hydroxide 作用下， 以 甲醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 56.5h， 生成 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
  参考文献：
  名称：

  Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents

  摘要：

  DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K-i of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC50 of 0.42 mu M. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.

  DOI：

  10.1021/jm101488z

文献信息

• Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor
  作者：Ronald Knegtel、Jean-Damien Charrier、Steven Durrant、Chris Davis、Michael O’Donnell、Pierre Storck、Somhairle MacCormick、David Kay、Joanne Pinder、Anisa Virani、Heather Twin、Matthew Griffiths、Philip Reaper、Peter Littlewood、Steve Young、Julian Golec、John Pollard

  DOI：10.1021/acs.jmedchem.9b00426

  日期：2019.6.13

  The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier et al. (J. Med. Chem. 2011, 54, 2320-2330, DOI: ).
• Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents
  作者：Jean-Damien Charrier、Steven J. Durrant、Julian M. C. Golec、David P. Kay、Ronald M. A. Knegtel、Somhairle MacCormick、Michael Mortimore、Michael E. O'Donnell、Joanne L. Pinder、Philip M. Reaper、Alistair P. Rutherford、Paul S. H. Wang、Stephen C. Young、John R. Pollard

  DOI：10.1021/jm101488z

  日期：2011.4.14

  DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K-i of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC50 of 0.42 mu M. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.