3-amino-N-cyclohexyl-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxamide | 1286238-58-1

• 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: 3-amino-N-cyclohexyl-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxamide
• 英文别名: 3-amino-N-cyclohexyl-6-(4-methylsulfonylphenyl)pyrazine-2-carboxamide
• CAS: 1286238-58-1
• 化学式: C₁₈H₂₂N₄O₃S
• 分子量: 374.464
• InChiKey: GXEFZNAFUGYJGB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 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 bis-triphenylphosphine-palladium(II) chloride 、 N-溴代丁二酰亚胺(NBS) 、 氰基磷酸二乙酯 、 sodium carbonate 、 N,N-二异丙基乙胺 作用下， 以 乙二醇二甲醚 、 乙腈 为溶剂， 反应 27.17h， 生成 3-amino-N-cyclohexyl-6-(4-(methylsulfonyl)phenyl)pyrazine-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

• 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.