2-(3-(2-tert-butoxy-2-oxoethyl)-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid | 291778-37-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(3-(2-tert-butoxy-2-oxoethyl)-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid
• CAS: 291778-37-5
• 化学式: C₁₃H₁₈N₂O₆
• 分子量: 298.296
• InChiKey: JIHKQTMIKXXWOZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.26
• 重原子数：
  21.0
• 可旋转键数：
  4.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  107.6
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  2-(3-(2-tert-butoxy-2-oxoethyl)-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid 、 (1S)-L-valyl-N-<1-<(2-benzoxazolyl)hydroxymethyl>-2-methylpropyl>-L-prolinamide 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 生成 tert-butyl 2-(3-(2-(((2S)-1-((2S)-2-(((2S)-1-(benzo[d]oxazol-2-yl)-1-hydroxy-3-methylbutan-2-yl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)acetate
  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
• 作为产物：
  描述：

  benzyl 2-(3-(2-tert-butoxy-2-oxoethyl)-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 以89%的产率得到2-(3-(2-tert-butoxy-2-oxoethyl)-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid
  参考文献：
  名称：

  Human Neutrophil Elastase Phosphonic Inhibitors with Improved Potency of Action

  摘要：

  Herein, we present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of alpha-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, was also demonstrated. We also describe the preparation of single peptide diastereomers. The most active and selective compound developed possessed a k(inact)/K-1 of 2353000 M-1 s(-1), which is the most potent irreversible peptidyl inhibitor of human neutrophil elastase reported to date. The peptidyl inhibitors were demonstrated to be stable in PBS buffer and human plasma, as were their complexes with HNE.

  DOI：

  10.1021/jm300599x