4-[2-amino-6-(3-amino-1H-indazol-6-yl)-4-pyrimidinyl]-N-phenyl-2-morpholinecarboxamide | 1271023-10-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: 4-[2-amino-6-(3-amino-1H-indazol-6-yl)-4-pyrimidinyl]-N-phenyl-2-morpholinecarboxamide
• 英文别名: (2R)-4-[2-amino-6-(3-amino-1H-indazol-6-yl)pyrimidin-4-yl]-N-phenylmorpholine-2-carboxamide
• CAS: 1271023-10-9
• 化学式: C₂₂H₂₂N₈O₂
• 分子量: 430.469
• InChiKey: NCSQDKMOKNQGSG-GOSISDBHSA-N

物化性质

• 密度：
  1.467±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-Boc-2-吗啉甲酸 在 N-甲基吗啉 、 四(三苯基膦)钯 、 碳酸氢钠 、 1-羟基苯并三唑 、 一水合肼 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 异丙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 4-[2-amino-6-(3-amino-1H-indazol-6-yl)-4-pyrimidinyl]-N-phenyl-2-morpholinecarboxamide 、 4-[2-amino-6-(3-amino-1H-indazol-6-yl)-4-pyrimidinyl]-N-phenyl-2-morpholinecarboxamide
  参考文献：
  名称：

  Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

  摘要：

  Phosphoinositide-dependent protein kinase-1 (PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDKI might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDKI inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OC1-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDKI and the potential pharmacological uses of a PDK1 inhibitor.

  DOI：

  10.1021/jm101527u

文献信息

• Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors
  作者：Jesús R. Medina、Christopher J. Becker、Charles W. Blackledge、Celine Duquenne、Yanhong Feng、Seth W. Grant、Dirk Heerding、William H. Li、William H. Miller、Stuart P. Romeril、Daryl Scherzer、Arthur Shu、Mark A. Bobko、Antony R. Chadderton、Melissa Dumble、Christine M. Gardiner、Seth Gilbert、Qi Liu、Sridhar K. Rabindran、Valery Sudakin、Hong Xiang、Pat G. Brady、Nino Campobasso、Paris Ward、Jeffrey M. Axten

  DOI：10.1021/jm101527u

  日期：2011.3.24

  Phosphoinositide-dependent protein kinase-1 (PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDKI might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDKI inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OC1-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDKI and the potential pharmacological uses of a PDK1 inhibitor.