2-(4-fluorophenyl)-N-(2-isonicotinoylphenyl)acetamide | 934560-45-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(4-fluorophenyl)-N-(2-isonicotinoylphenyl)acetamide
• 英文别名: 2-(4-fluorophenyl)-N-[2-(pyridine-4-carbonyl)phenyl]acetamide
• CAS: 934560-45-9
• 化学式: C₂₀H₁₅FN₂O₂
• 分子量: 334.35
• InChiKey: BXMNZOUCXZLSKQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  59.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(4-fluorophenyl)-N-(2-isonicotinoylphenyl)acetamide 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 反应 0.5h， 以451 mg的产率得到3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one
  参考文献：
  名称：

  3,4-二芳基喹啉酮作为p38alphaMAP激酶抑制剂的选择性的含义。

  摘要：

  在这项研究中，我们报告了MAP激酶抑制剂1、2和3在78种蛋白激酶（包括MAPK亚型p38（α，β，γ，δ），JNK1 / 2/3和ERK1）中的特异性谱。 / 2/8显示3-（4-氟苯基）-4-吡啶-4-基喹啉-2（1H）-一（1）对p38alphaMAPK具有高度选择性，IC（50）为1.8 microM。相反，除了p38alpha以外，异恶唑2和3还显着抑制JNK2 / 3和MAPK家族以外的其他激酶，例如PKA，PKD，Lck和CK1。通过使用序列比对和MAPK家族的不同成员的同源性模型，研究了确定p38alpha同工型的选择性的结合模式。对于1的铅优化，采用了一种简单的串联-布赫瓦尔德-阿尔道合成方法来对喹啉2（1H）-一个脚手架进行灵活的装饰。

  DOI：

  10.1016/j.bmcl.2007.12.073
• 作为产物：
  描述：

  N-(2-(hydroxy(4-pyridyl)methyl)phenyl)trimethylacetamide 在 盐酸 、 jones' reagent 、 五氯化磷 作用下， 以 乙醇 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 84.0h， 生成 2-(4-fluorophenyl)-N-(2-isonicotinoylphenyl)acetamide
  参考文献：
  名称：

  From Five- to Six-Membered Rings:  3,4-Diarylquinolinone as Lead for Novel p38MAP Kinase Inhibitors

  摘要：

  In this study we describe the design, synthesis, and biological evaluation of 3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one (5) as a new inhibitor of MAPK with a p38 alpha MAPK IC50 of 1.8 mu M. By keeping the common vicinal pyridine/4-F-phenyl pharmacophore, such as in prototypical imidazole 20 or isoxazole 13 but in 5 connected to the six-membered quinoline core, we were particularly interested in comparing biological activity, details of molecular geometry, and different binding modes of these compounds. Compounds 20 and 13 were active both in the p38 alpha- and JNK3-assay, whereas 5 was selective for p38 alpha, with no JNK3 inhibition. By comparing the X-ray structures of the compounds, we found a significantly larger distance between the pyridine and the 4-F-phenyl moiety in five-membered core structures relevant for ligand-protein interactions. Molecular modeling studies support the results based on differences in the ATP pockets of p38 alpha and JNK3. Because most five-membered core based p38 alpha inhibitors show also activity for JNK3, compound 5 is an interesting lead for selective p38 alpha inhibitors.

  DOI：

  10.1021/jm061097o

文献信息

• From Five- to Six-Membered Rings:  3,4-Diarylquinolinone as Lead for Novel p38MAP Kinase Inhibitors
  作者：Christian Peifer、Katrin Kinkel、Mohammed Abadleh、Dieter Schollmeyer、Stefan Laufer

  DOI：10.1021/jm061097o

  日期：2007.3.1

  In this study we describe the design, synthesis, and biological evaluation of 3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one (5) as a new inhibitor of MAPK with a p38 alpha MAPK IC50 of 1.8 mu M. By keeping the common vicinal pyridine/4-F-phenyl pharmacophore, such as in prototypical imidazole 20 or isoxazole 13 but in 5 connected to the six-membered quinoline core, we were particularly interested in comparing biological activity, details of molecular geometry, and different binding modes of these compounds. Compounds 20 and 13 were active both in the p38 alpha- and JNK3-assay, whereas 5 was selective for p38 alpha, with no JNK3 inhibition. By comparing the X-ray structures of the compounds, we found a significantly larger distance between the pyridine and the 4-F-phenyl moiety in five-membered core structures relevant for ligand-protein interactions. Molecular modeling studies support the results based on differences in the ATP pockets of p38 alpha and JNK3. Because most five-membered core based p38 alpha inhibitors show also activity for JNK3, compound 5 is an interesting lead for selective p38 alpha inhibitors.
• Implications for selectivity of 3,4-diarylquinolinones as p38αMAP kinase inhibitors
  作者：Christian Peifer、Robert Urich、Verena Schattel、Mohammed Abadleh、Marc Röttig、Oliver Kohlbacher、Stefan Laufer

  DOI：10.1016/j.bmcl.2007.12.073

  日期：2008.2

  kinases including the MAPK isoforms p38(alpha,beta,gamma,delta), JNK1/2/3, and ERK1/2/8 showing 3-(4-fluorophenyl)-4-pyridin-4-ylquinolin-2(1H)-one (1) to be highly selective for p38alphaMAPK with an IC(50) of 1.8 microM. In contrast, besides p38alpha the isoxazoles 2 and 3 significantly inhibited JNK2/3 and further kinases beyond the MAPK family such as PKA, PKD, Lck, and CK1. By using sequence alignment

  在这项研究中，我们报告了MAP激酶抑制剂1、2和3在78种蛋白激酶（包括MAPK亚型p38（α，β，γ，δ），JNK1 / 2/3和ERK1）中的特异性谱。 / 2/8显示3-（4-氟苯基）-4-吡啶-4-基喹啉-2（1H）-一（1）对p38alphaMAPK具有高度选择性，IC（50）为1.8 microM。相反，除了p38alpha以外，异恶唑2和3还显着抑制JNK2 / 3和MAPK家族以外的其他激酶，例如PKA，PKD，Lck和CK1。通过使用序列比对和MAPK家族的不同成员的同源性模型，研究了确定p38alpha同工型的选择性的结合模式。对于1的铅优化，采用了一种简单的串联-布赫瓦尔德-阿尔道合成方法来对喹啉2（1H）-一个脚手架进行灵活的装饰。