O²-acetoxymethyl 1-{N-[2-(2-[4-(isobutyl)phenyl]propanoyloxy)ethyl]-N-methylamino}diazen-1-ium-1,2-diolate

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: O²-acetoxymethyl 1-{N-[2-(2-[4-(isobutyl)phenyl]propanoyloxy)ethyl]-N-methylamino}diazen-1-ium-1,2-diolate
• 英文别名: (Z)-acetyloxymethoxyimino-[methyl-[2-[2-[4-(2-methylpropyl)phenyl]propanoyloxy]ethyl]amino]-oxidoazanium
• 化学式: C₁₉H₂₉N₃O₆
• 分子量: 395.456
• InChiKey: SEIAPNZQAXURTQ-XDOYNYLZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  28
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  106
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  布洛芬 、 O²-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazen-1-ium-1,2-diolate 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以60%的产率得到O²-acetoxymethyl 1-{N-[2-(2-[4-(isobutyl)phenyl]propanoyloxy)ethyl]-N-methylamino}diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  O2-Acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO–NSAIDs): Synthesis, nitric oxide release, and biological evaluation studies

  摘要：

  A novel group of O-2-acetoxymethyl-protected diazeniumdiolate-based non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) were synthesized by esterifying the carboxylate group of aspirin, ibuprofen, or indomethacin with O-2-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazeniumdiolate. The resulting nitric oxide ((NO)-N-center dot)-releasing prodrugs (7-9) did not exhibit in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50S > 100 mu M), In contrast, prodrugs 7 and 8 significantly decreased carrageenan-induced rat paw edema showing enhanced in vivo anti-inflammatory activities (ID50's = 552 and 174 mu mol/kg, respectively) relative to those of the parent NSAIDs aspirin (ID50 = 714 mu mol/kg) and ibuprofen (ID50 = 326 mu mol/kg). The rate of porcine liver esterase-mediated (NO)-N-center dot release from prodrugs 7-9 (2 mol of (NO)-N-center dot/mol of test compound in 0.6-6.5 min) was substantially higher compared to that observed without enzymatic catalysis (about 1 mol of (NO)-N-center dot/mol of test compound in 40-48 h). These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo activation (hydrolysis) by esterases. Data acquired in an in vivo ulcer index (UI) assay showed that NONO-aspirin (UI = 0.8), NONO-indomethacin (UI = 1.3), and particularly NONO-ibuprofen (UI = 0) were significantly less ulcerogenic compared to the parent drugs aspirin (UI = 57), ibuprofen (UI = 46) or indomethacin (UI = 34) at equimolar doses. The release of aspirin and (NO)-N-center dot from the NONO-aspirin (7) prodrug constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2007.05.009

文献信息

• O2-Acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO–NSAIDs): Synthesis, nitric oxide release, and biological evaluation studies
  作者：Carlos A. Velázquez、P.N. Praveen Rao、Michael L. Citro、Larry K. Keefer、Edward E. Knaus

  DOI：10.1016/j.bmc.2007.05.009

  日期：2007.7

  A novel group of O-2-acetoxymethyl-protected diazeniumdiolate-based non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) were synthesized by esterifying the carboxylate group of aspirin, ibuprofen, or indomethacin with O-2-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazeniumdiolate. The resulting nitric oxide ((NO)-N-center dot)-releasing prodrugs (7-9) did not exhibit in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50S > 100 mu M), In contrast, prodrugs 7 and 8 significantly decreased carrageenan-induced rat paw edema showing enhanced in vivo anti-inflammatory activities (ID50's = 552 and 174 mu mol/kg, respectively) relative to those of the parent NSAIDs aspirin (ID50 = 714 mu mol/kg) and ibuprofen (ID50 = 326 mu mol/kg). The rate of porcine liver esterase-mediated (NO)-N-center dot release from prodrugs 7-9 (2 mol of (NO)-N-center dot/mol of test compound in 0.6-6.5 min) was substantially higher compared to that observed without enzymatic catalysis (about 1 mol of (NO)-N-center dot/mol of test compound in 40-48 h). These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo activation (hydrolysis) by esterases. Data acquired in an in vivo ulcer index (UI) assay showed that NONO-aspirin (UI = 0.8), NONO-indomethacin (UI = 1.3), and particularly NONO-ibuprofen (UI = 0) were significantly less ulcerogenic compared to the parent drugs aspirin (UI = 57), ibuprofen (UI = 46) or indomethacin (UI = 34) at equimolar doses. The release of aspirin and (NO)-N-center dot from the NONO-aspirin (7) prodrug constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. Published by Elsevier Ltd.