2-chloro-3-nitro-4H-pyrido[1,2-a]pyrimidin-4-one | 349573-14-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2-chloro-3-nitro-4H-pyrido[1,2-a]pyrimidin-4-one
• 英文别名: 2-chloro-3-nitropyrido[1,2-a]pyrimidin-4-one
• CAS: 349573-14-4
• 化学式: C₈H₄ClN₃O₃
• mdl: MFCD00448894
• 分子量: 225.591
• InChiKey: HRMUOPNLPLATOR-UHFFFAOYSA-N

物化性质

• 沸点：
  299.7±50.0 °C(Predicted)
• 密度：
  1.71±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  78.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2,6-二甲基吗啉 、 2-chloro-3-nitro-4H-pyrido[1,2-a]pyrimidin-4-one 在 氯化铵 、 锌 作用下， 以 甲醇 为溶剂， 生成 Kinase inhibitor, A1
  参考文献：
  名称：

  De Novo Design of Protein Kinase Inhibitors by in Silico Identification of Hinge Region-Binding Fragments

  摘要：

  Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.

  DOI：

  10.1021/cb300729y
• 作为产物：
  描述：

  2-氨基吡啶 、 丙二酸二乙酯 在 三氯氧磷 、 硫酸 、 硝酸 作用下， 生成 2-chloro-3-nitro-4H-pyrido[1,2-a]pyrimidin-4-one
  参考文献：
  名称：

  De Novo Design of Protein Kinase Inhibitors by in Silico Identification of Hinge Region-Binding Fragments

  摘要：

  Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.

  DOI：

  10.1021/cb300729y

文献信息

• <i>De Novo</i> Design of Protein Kinase Inhibitors by <i>in Silico</i> Identification of Hinge Region-Binding Fragments
  作者：Robert Urich、Grant Wishart、Michael Kiczun、André Richters、Naomi Tidten-Luksch、Daniel Rauh、Brad Sherborne、Paul G. Wyatt、Ruth Brenk

  DOI：10.1021/cb300729y

  日期：2013.5.17

  Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.