O2-acetoxymethyl-1-{N-[2-(2-(4-(1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl)phenyl)acetoxy)ethyl]-N-methylamino}diazen-1-ium-1,2-diolate | 1186423-59-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: O2-acetoxymethyl-1-{N-[2-(2-(4-(1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl)phenyl)acetoxy)ethyl]-N-methylamino}diazen-1-ium-1,2-diolate
• 英文别名: acetyloxymethoxyimino-[methyl-[2-[2-[4-[2-(4-sulfamoylphenyl)-5-(trifluoromethyl)pyrazol-3-yl]phenyl]acetyl]oxyethyl]amino]-oxidoazanium
• CAS: 1186423-59-5
• 化学式: C₂₄H₂₅F₃N₆O₈S
• 分子量: 614.559
• InChiKey: KSHUHZPSDIAWAJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  42
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  193
• 氢给体数：
  1
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  O2-acetoxymethyl-1-[N-(2-methylsulfonyloxyethyl)-N-methylamino]diazen-1-ium-1,2-diolate 、 5-(4-carboxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole 在 sodium carbonate 作用下， 以 六甲基磷酰三胺 为溶剂， 反应 96.0h， 以36%的产率得到O2-acetoxymethyl-1-{N-[2-(2-(4-(1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl)phenyl)acetoxy)ethyl]-N-methylamino}diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-carboxymethylphenyl)-1-(4-methanesulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its aminosulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies

  摘要：

  A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs) wherein an O-2-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (13a-b), or O-2-acetoxymethyl-1-(2-methylpyrrolidin-1-yl)diazen-1-ium-1,2-diolate (16a-b), NO-donor moiety was covalently coupled to the COOH group of 5-(4-carboxymethylphenyl)-1-(4-methane(amino) sulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (11a-b) was synthesized. The percentage of NO released from these diazen-1-ium-1,2-diolates was significantly higher (59.6-74.6% of the theoretical maximal release of 2 molecules of NO/molecule of the parent hybrid ester prodrug) upon incubation in the presence of rat serum, relative to incubation with phosphate buffer (PBS) at pH 7.4 (5.0-7.2% range). These incubation studies suggest that both NO and the AI compound would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. All compounds were weak inhibitors of the COX-1 isozyme (IC50 = 8.1-65.2 mu M range) and modest inhibitors of the COX-2 isozyme (IC50 = 0.9-4.6 mu M range). The most potent parent aminosulfonyl compound 11b exhibited AI activity that was about sixfold greater than that for aspirin and threefold greater than that for ibuprofen. The ester prodrugs 13b, 16b exhibited similar AI activity to that exhibited by the more potent parent acid 11b when the same oral mu mol/kg dose was administered. These studies indicate hybrid ester AI/NO donor prodrugs of this type (NONO-coxibs) constitute a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.05.046

文献信息

• Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-carboxymethylphenyl)-1-(4-methanesulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its aminosulfonyl analog: Synthesis, biological evaluation and nitric oxide release studies
  作者：Khaled R.A. Abdellatif、Morshed Alam Chowdhury、Ying Dong、Dipankar Das、Gang Yu、Carlos Velázquez、Mavanur R. Suresh、Edward E. Knaus

  DOI：10.1016/j.bmc.2009.05.046

  日期：2009.7

  A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs) wherein an O-2-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (13a-b), or O-2-acetoxymethyl-1-(2-methylpyrrolidin-1-yl)diazen-1-ium-1,2-diolate (16a-b), NO-donor moiety was covalently coupled to the COOH group of 5-(4-carboxymethylphenyl)-1-(4-methane(amino) sulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (11a-b) was synthesized. The percentage of NO released from these diazen-1-ium-1,2-diolates was significantly higher (59.6-74.6% of the theoretical maximal release of 2 molecules of NO/molecule of the parent hybrid ester prodrug) upon incubation in the presence of rat serum, relative to incubation with phosphate buffer (PBS) at pH 7.4 (5.0-7.2% range). These incubation studies suggest that both NO and the AI compound would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. All compounds were weak inhibitors of the COX-1 isozyme (IC50 = 8.1-65.2 mu M range) and modest inhibitors of the COX-2 isozyme (IC50 = 0.9-4.6 mu M range). The most potent parent aminosulfonyl compound 11b exhibited AI activity that was about sixfold greater than that for aspirin and threefold greater than that for ibuprofen. The ester prodrugs 13b, 16b exhibited similar AI activity to that exhibited by the more potent parent acid 11b when the same oral mu mol/kg dose was administered. These studies indicate hybrid ester AI/NO donor prodrugs of this type (NONO-coxibs) constitute a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects. (C) 2009 Elsevier Ltd. All rights reserved.