(1S)-L-valyl-N-<1-<(2-benzoxazolyl)hydroxymethyl>-2-methylpropyl>-L-prolinamide | 291779-25-4

• 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: (1S)-L-valyl-N-<1-<(2-benzoxazolyl)hydroxymethyl>-2-methylpropyl>-L-prolinamide
• 英文别名: L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide；(2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-[(2S)-1-(1,3-benzoxazol-2-yl)-1-hydroxy-3-methylbutan-2-yl]pyrrolidine-2-carboxamide
• CAS: 291779-25-4
• 化学式: C₂₂H₃₂N₄O₄
• 分子量: 416.52
• InChiKey: LHCPMPIRNJVYPL-PYUTUISCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  122
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1S)-L-valyl-N-<1-<(2-benzoxazolyl)hydroxymethyl>-2-methylpropyl>-L-prolinamide 在 4-二甲氨基吡啶 、 戴斯-马丁氧化剂 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 叔丁醇 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 49.5h， 生成 <<4-<<(methylsulfonyl)amino>carbonyl>benzoyl>-L-valyl>-N-<1-<(2-benzoxazolyl)carbonyl>-2-methylpropyl>-L-prolinamide
  参考文献：
  名称：

  Peptidyl .alpha.-ketoheterocyclic inhibitors of human neutrophil elastase. 3. In vitro and in vivo potency of a series of peptidyl .alpha.-ketobenzoxazoles

  摘要：

  A series of peptidyl alpha-ketobenzoxazoles were synthesized and evaluated for their in vitro and in vivo inhibition of human neutrophil elastase (HNE). These compounds inhibit HNE by forming both a covalent bond between the ketone carbonyl carbon atom and the hydroxyl group of Ser-195 and a hydrogen bond between the benzoxazole nitrogen atom and His-57. Appending to the parent benzoxazole ring a variety of substituents which spanned a range of physicochemical properties had only a modest effect on in, vitro potency (K-i = 3-0.4 nM). This apparent lack of a significant effect is believed to result from the fact that any increased ketone carbonyl activation by the ring substituent is counter balanced by a corresponding decrease in the hydrogen-bonding ability of the benzoxazole nitrogen atom. In contrast to the results in vitro, maximizing in vive activity was critically dependent upon the choice of the benzoxazole ring substituent. Several substituted peptidyl alpha-ketobenzoxazoles effectively inhibited HNE-induced lung injury when administered intratracheally 24 h prior to the enzyme.

  DOI：

  10.1021/jm00020a011
• 作为产物：
  描述：

  N-Benzyloxycarbonyl-L-valyl-L-prolyl-L-valinal 在 palladium on activated charcoal 水 、 氢气 、 乙酰氯 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 为溶剂， 25.0~60.0 ℃ 、344.73 kPa 条件下， 反应 30.5h， 生成 (1S)-L-valyl-N-<1-<(2-benzoxazolyl)hydroxymethyl>-2-methylpropyl>-L-prolinamide
  参考文献：
  名称：

  Peptidyl .alpha.-ketoheterocyclic inhibitors of human neutrophil elastase. 3. In vitro and in vivo potency of a series of peptidyl .alpha.-ketobenzoxazoles

  摘要：

  A series of peptidyl alpha-ketobenzoxazoles were synthesized and evaluated for their in vitro and in vivo inhibition of human neutrophil elastase (HNE). These compounds inhibit HNE by forming both a covalent bond between the ketone carbonyl carbon atom and the hydroxyl group of Ser-195 and a hydrogen bond between the benzoxazole nitrogen atom and His-57. Appending to the parent benzoxazole ring a variety of substituents which spanned a range of physicochemical properties had only a modest effect on in, vitro potency (K-i = 3-0.4 nM). This apparent lack of a significant effect is believed to result from the fact that any increased ketone carbonyl activation by the ring substituent is counter balanced by a corresponding decrease in the hydrogen-bonding ability of the benzoxazole nitrogen atom. In contrast to the results in vitro, maximizing in vive activity was critically dependent upon the choice of the benzoxazole ring substituent. Several substituted peptidyl alpha-ketobenzoxazoles effectively inhibited HNE-induced lung injury when administered intratracheally 24 h prior to the enzyme.

  DOI：

  10.1021/jm00020a011

文献信息

• Heterocyclic compounds, intermediates thereof and elastase inhibitors
  申请人：Dainippon Pharmaceutical Co., Ltd.

  公开号：US06835714B1

  公开（公告）日：2004-12-28

  The present invention relates to a heterocyclic compound of the following formula (I-a), its ester, or a salt thereof, and a human neutrophilic elastase inhibitor containing the same as the active ingredient, etc. wherein A and B are the same or different and each is a lower alkylene group being optionally substituted by an oxo group, D is a heteromonocyclic or heterobicyclic group being optionally substituted by an oxo group, R1 and R2 are the same or different and each is a lower alkyl group, R3 and R4 are different from each other, and each is a hydrogen atom or a hydroxy group, or both combine together to form an oxo group, and R5 is 2-benzoxazolyl, trifluoromethyl, benzylamino-carbonyl, etc.

  本发明涉及以下式（I-a）的杂环化合物，其酯或其盐，以及含有其作为活性成分的人类嗜中性粒细胞弹性蛋白酶抑制剂等。其中，A和B相同或不同，每个都是可选地被氧代团取代的较低烷基烷基，D是可选地被氧代团取代的杂单环或杂双环基团，R1和R2相同或不同，每个都是较低烷基烷基，R3和R4不同，并且每个都是氢原子或羟基，或两者结合形成氧代团，R5是2-苯并噁唑基，三氟甲基，苯甲氨基羰基等。
• HETEROCYCLIC COMPOUNDS, INTERMEDIATES THEREOF AND ELASTASE INHIBITORS
  申请人：Dainippon Pharmaceutical Co., Ltd.

  公开号：EP1157998B1

  公开（公告）日：2004-02-11
• 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.
• US6835714B1
  申请人：——

  公开号：US6835714B1

  公开（公告）日：2004-12-28
• Peptidyl .alpha.-ketoheterocyclic inhibitors of human neutrophil elastase. 3. In vitro and in vivo potency of a series of peptidyl .alpha.-ketobenzoxazoles
  作者：Philip D. Edwards、Mark A. Zottola、Matthew Davis、Joseph Williams、Paul A. Tuthill

  DOI：10.1021/jm00020a011

  日期：1995.9

  A series of peptidyl alpha-ketobenzoxazoles were synthesized and evaluated for their in vitro and in vivo inhibition of human neutrophil elastase (HNE). These compounds inhibit HNE by forming both a covalent bond between the ketone carbonyl carbon atom and the hydroxyl group of Ser-195 and a hydrogen bond between the benzoxazole nitrogen atom and His-57. Appending to the parent benzoxazole ring a variety of substituents which spanned a range of physicochemical properties had only a modest effect on in, vitro potency (K-i = 3-0.4 nM). This apparent lack of a significant effect is believed to result from the fact that any increased ketone carbonyl activation by the ring substituent is counter balanced by a corresponding decrease in the hydrogen-bonding ability of the benzoxazole nitrogen atom. In contrast to the results in vitro, maximizing in vive activity was critically dependent upon the choice of the benzoxazole ring substituent. Several substituted peptidyl alpha-ketobenzoxazoles effectively inhibited HNE-induced lung injury when administered intratracheally 24 h prior to the enzyme.