tert-butyl ((2S)-1-((2S)-2-((1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

• 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: tert-butyl ((2S)-1-((2S)-2-((1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate
• 英文别名: Boc-L-Val-L-Pro-Val^P(OC₆H₄-4-SCH₃)₂；tert-butyl (S)-1-((S)-2-((R,S)-1-(bis(4-(methylthio)phenoxy)-phosphoryl)-2-methylpropylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate；tert-butyl N-[(2S)-1-[(2S)-2-[[1-bis(4-methylsulfanylphenoxy)phosphoryl-2-methylpropyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
• 化学式: C₃₃H₄₈N₃O₇PS₂
• 分子量: 693.866
• InChiKey: MYIQHDSRNXKCMI-SRBHEWTHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  46
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  174
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl ((2S)-1-((2S)-2-((1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 14.0h， 生成 tert-butyl 2-(4-(2-((S)-1-((S)-2-((S)-1-(bis(4-(methylthio)phenoxy)-phosphoryl)-2-methylpropylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethoxy)phenoxy)acetate
  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
• 作为产物：
  描述：

  4-(甲硫基)苯酚 在 氢溴酸 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 三氯化磷 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 36.0h， 生成 tert-butyl ((2S)-1-((2S)-2-((1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate
  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

文献信息

• Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase
  作者：Karolina Torzyk-Jurowska、Jaroslaw Ciekot、Lukasz Winiarski

  DOI：10.3390/molecules29051120

  日期：——

  the HNE inhibitor with kinact/KI value over 2,000,000 [M−1s−1]. In order to optimize its structure, over 100 novel tripeptidyl derivatives of α-aminoalkylphosphonate diaryl esters were synthesized, and their activity toward HNE was checked. To confirm the selectivity of the resultant compounds, several of the most active were additionally checked against the two other neutrophil proteases: proteinase

  尽管经过多年的研究，人类中性粒细胞弹性蛋白酶（HNE）仍然是许多研究人员感兴趣的领域。这种中性粒细胞丝氨酸蛋白酶的多功能代表是人体内发现的最具破坏性的酶之一，可以降解大部分细胞外基质。 HNE 的过度表达或失调可能导致多种炎症性疾病的发生。之前，我们提出了 kinact/KI 值超过 2,000,000 [M−1s−1] 的 HNE 抑制剂。为了优化其结构，合成了100多种新型α-氨基烷基膦酸二芳基酯三肽基衍生物，并检查了它们对HNE的活性。为了确认所得化合物的选择性，还针对另外两种中性粒细胞蛋白酶（蛋白酶 3 和组织蛋白酶 G）检查了几种最活跃的化合物。所开发的修饰使我们能够获得一种对人中性粒细胞弹性蛋白酶具有显着增强的抑制活性的化合物。对组织蛋白酶 G 具有选择性，但对蛋白酶 3 没有选择性。
• Human Neutrophil Elastase Phosphonic Inhibitors with Improved Potency of Action
  作者：Łukasz Winiarski、Józef Oleksyszyn、Marcin Sieńczyk

  DOI：10.1021/jm300599x

  日期：2012.7.26

  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.