3-((2-(pyridine-2-yl)ethyl(methyl)amino)methyl)-2-methyl-4-isopropyl-1-phenyl-3-pyrazolin-5-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-((2-(pyridine-2-yl)ethyl(methyl)amino)methyl)-2-methyl-4-isopropyl-1-phenyl-3-pyrazolin-5-one
• 英文别名: 1-Methyl-5-[[methyl(2-pyridin-2-ylethyl)amino]methyl]-2-phenyl-4-propan-2-ylpyrazol-3-one；1-methyl-5-[[methyl(2-pyridin-2-ylethyl)amino]methyl]-2-phenyl-4-propan-2-ylpyrazol-3-one
• 化学式: C₂₂H₂₈N₄O
• 分子量: 364.491
• InChiKey: ROJQUWJHFVVHMW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  39.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  异丙安替比林 在 溴 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 丙酮 为溶剂， 反应 1.0h， 生成 3-((2-(pyridine-2-yl)ethyl(methyl)amino)methyl)-2-methyl-4-isopropyl-1-phenyl-3-pyrazolin-5-one
  参考文献：
  名称：

  Propyphenazone-Based Analogues as Prodrugs and Selective Cyclooxygenase-2 Inhibitors

  摘要：

  Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.

  DOI：

  10.1021/ml500156v

文献信息

• Propyphenazone-Based Analogues as Prodrugs and Selective Cyclooxygenase-2 Inhibitors
  作者：Mohamed F. Radwan、Kevin N. Dalby、Tamer S. Kaoud

  DOI：10.1021/ml500156v

  日期：2014.9.11

  Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.