3-[(2R)-1-(dimethylamino)propan-2-yl]oxy-5-[[4-(methylamino)pyridin-2-yl]amino]pyrazine-2-carbonitrile | 1404095-19-7

• 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-[(2R)-1-(dimethylamino)propan-2-yl]oxy-5-[[4-(methylamino)pyridin-2-yl]amino]pyrazine-2-carbonitrile
• CAS: 1404095-19-7
• 化学式: C₁₆H₂₁N₇O
• 分子量: 327.389
• InChiKey: SIMIJFXHWJHJLE-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  99
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  R-(-)-1-二甲氨基-2-丙醇 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium hydride 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 、 mineral oil 为溶剂， 反应 15.5h， 生成 3-[(2R)-1-(dimethylamino)propan-2-yl]oxy-5-[[4-(methylamino)pyridin-2-yl]amino]pyrazine-2-carbonitrile
  参考文献：
  名称：

  Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors

  摘要：

  Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment based drug design and optimized for CHK1 potency and high selectivity using a cell based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent

  DOI：

  10.1021/jm3012933

文献信息

• Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors
  作者：Michael Lainchbury、Thomas P. Matthews、Tatiana McHardy、Kathy J. Boxall、Michael I. Walton、Paul D. Eve、Angela Hayes、Melanie R. Valenti、Alexis K. de Haven Brandon、Gary Box、G. Wynne Aherne、John C. Reader、Florence I. Raynaud、Suzanne A. Eccles、Michelle D. Garrett、Ian Collins

  DOI：10.1021/jm3012933

  日期：2012.11.26

  Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment based drug design and optimized for CHK1 potency and high selectivity using a cell based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent