3-amino-6-(4-(methylsulfinyl)phenyl)-N-phenylpyrazine-2-carboxamide | 1286238-49-0

• 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-(methylsulfinyl)phenyl)-N-phenylpyrazine-2-carboxamide
• 英文别名: 3-amino-6-(4-methylsulfinylphenyl)-N-phenylpyrazine-2-carboxamide
• CAS: 1286238-49-0
• 化学式: C₁₈H₁₆N₄O₂S
• 分子量: 352.417
• InChiKey: XKSHJVRSLGTDOV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-氨基-6-溴吡嗪-2-甲酸 在 4-二甲氨基吡啶 、 sodium carbonate 、 N,N-二异丙基乙胺 、 N,N'-羰基二咪唑 作用下， 以 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.5h， 生成 3-amino-6-(4-(methylsulfinyl)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

• [EN] NEW ATR INHIBITORS FOR THE USE IN CANCER THERAPY<br/>[FR] NOUVEAUX INHIBITEURS D'ATR DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DU CANCER
  申请人：RHEINISCH WESTFAELISCHE TECHNISCHE HOCHSCHULE AACHEN RWTH

  公开号：WO2018029117A1

  公开（公告）日：2018-02-15

  This invention relates to pyrazine compounds having a sulfilimine or sulfoximine groups and to the use of said compounds for treating cancer. Furthermore the invention relates to combination treatment using said compounds. Finally, the present invention also relates to pharmaceutically acceptable composition comprising the compounds of this invention, and processes for preparing the compounds of this invention.

  本发明涉及具有磺酰亚胺或亚磺酰氧亚胺基团的吡嗪化合物及其用于治疗癌症的用途。此外，本发明涉及使用上述化合物进行联合治疗的方法。最后，本发明还涉及包含本发明化合物的药学上可接受的组合物，以及制备本发明化合物的方法。
• 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.