N-{[3-(carboxymethyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]acetyl}-L-valyl-N-[(3S)-1-methoxy-4-methyl-1,2-dioxopentan-3-yl]-L-prolinamide | 291778-95-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: N-{[3-(carboxymethyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]acetyl}-L-valyl-N-[(3S)-1-methoxy-4-methyl-1,2-dioxopentan-3-yl]-L-prolinamide
• 英文别名: Tripeptide-based inhibitor, 14r；2-[3-[2-[[(2S)-1-[(2S)-2-[[(3S)-1-methoxy-4-methyl-1,2-dioxopentan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-2-oxoethyl]-2,6-dioxopyrimidin-1-yl]acetic acid
• CAS: 291778-95-5
• 化学式: C₂₅H₃₅N₅O₁₀
• 分子量: 565.58
• InChiKey: MUEIHMGFQGXGLO-YSSFQJQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  200
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以43 mg的产率得到N-{[3-(carboxymethyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]acetyl}-L-valyl-N-[(3S)-1-methoxy-4-methyl-1,2-dioxopentan-3-yl]-L-prolinamide
  参考文献：
  名称：

  Development of a highly water-soluble peptide-based human neutrophil elastase inhibitor; AE-3763 for treatment of acute organ injury

  摘要：

  A series of peptide-based transition-state human neutrophil elastase (HNE) inhibitors with N-terminal acidic moieties were synthesized and their inhibitory activity against HNE was evaluated both in vitro and in vivo. Our results show that compounds containing cyclic amide bridged acidic moieties at the N-terminal have not only improved water solubility but also high in vivo potency. Among these compounds, AE-3763 showed remarkable efficacy in hamster models of elastase-induced lung hemorrhage and lipopolysaccharide (LPS)-induced lung injury as well as in a mouse model of LPS/galactosamine-induced acute multiple organ dysfunctions. The water solubility of AE-3763 (>1000 mg/ml in H(2)O) was also far superior to that of any of the other compounds synthesized. Thus, it is believed that AE-3763 would be useful for treatment of HNE-associated respiratory disorders, such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and acute exacerbation of chronic obstructive pulmonary disease (COPD). (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.09.020

文献信息

• Development of a highly water-soluble peptide-based human neutrophil elastase inhibitor; AE-3763 for treatment of acute organ injury
  作者：Yasunao Inoue、Tomoki Omodani、Ryotaro Shiratake、Hiroshi Okazaki、Akemi Kuromiya、Taeko Kubo、Fuminori Sato

  DOI：10.1016/j.bmc.2009.09.020

  日期：2009.11

  A series of peptide-based transition-state human neutrophil elastase (HNE) inhibitors with N-terminal acidic moieties were synthesized and their inhibitory activity against HNE was evaluated both in vitro and in vivo. Our results show that compounds containing cyclic amide bridged acidic moieties at the N-terminal have not only improved water solubility but also high in vivo potency. Among these compounds, AE-3763 showed remarkable efficacy in hamster models of elastase-induced lung hemorrhage and lipopolysaccharide (LPS)-induced lung injury as well as in a mouse model of LPS/galactosamine-induced acute multiple organ dysfunctions. The water solubility of AE-3763 (>1000 mg/ml in H(2)O) was also far superior to that of any of the other compounds synthesized. Thus, it is believed that AE-3763 would be useful for treatment of HNE-associated respiratory disorders, such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and acute exacerbation of chronic obstructive pulmonary disease (COPD). (C) 2009 Elsevier Ltd. All rights reserved.