methyl 4-methyl-3-(1-phenyl-5-propyl-1H-pyrazole-4-carboxamido)benzoate

• 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: methyl 4-methyl-3-(1-phenyl-5-propyl-1H-pyrazole-4-carboxamido)benzoate
• 英文别名: Methyl 4-methyl-3-[(1-phenyl-5-propylpyrazole-4-carbonyl)amino]benzoate；methyl 4-methyl-3-[(1-phenyl-5-propylpyrazole-4-carbonyl)amino]benzoate
• 化学式: C₂₂H₂₃N₃O₃
• 分子量: 377.443
• InChiKey: AFZHEBHUAJCFKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  73.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4-methyl-3-(1-phenyl-5-propyl-1H-pyrazole-4-carboxamido)benzoate 在 水 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 16.0h， 以84%的产率得到4-methyl-3-(1-phenyl-5-propyl-1H-pyrazole-4-carboxamido)benzoic acid
  参考文献：
  名称：

  Discovery and Characterization of MAPK-activated Protein Kinase-2 Prevention of Activation Inhibitors

  摘要：

  Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structureactivity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38 alpha of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38 alpha but unexpectedly with higher affinity in the p38 alpha-MK2 complex compared with p38 alpha alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38 alpha inhibitors.

  DOI：

  10.1021/jm501038s
• 作为产物：
  描述：

  3-氨基-4-甲基苯甲酸甲酯 、 1-苯基-5-丙基-1H-吡唑-4-羧酸 在 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.17h， 以56%的产率得到methyl 4-methyl-3-(1-phenyl-5-propyl-1H-pyrazole-4-carboxamido)benzoate
  参考文献：
  名称：

  Discovery and Characterization of MAPK-activated Protein Kinase-2 Prevention of Activation Inhibitors

  摘要：

  Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structureactivity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38 alpha of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38 alpha but unexpectedly with higher affinity in the p38 alpha-MK2 complex compared with p38 alpha alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38 alpha inhibitors.

  DOI：

  10.1021/jm501038s

文献信息

• Discovery and Characterization of MAPK-activated Protein Kinase-2 Prevention of Activation Inhibitors
  作者：John G. Cumming、Judit É. Debreczeni、Fredrik Edfeldt、Emma Evertsson、Martin Harrison、Geoffrey A. Holdgate、Michael J. James、Scott G. Lamont、Keith Oldham、Jane E. Sullivan、Stuart L. Wells

  DOI：10.1021/jm501038s

  日期：2015.1.8

  Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structureactivity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38 alpha of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38 alpha but unexpectedly with higher affinity in the p38 alpha-MK2 complex compared with p38 alpha alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38 alpha inhibitors.