N-(carbobenzyloxy)-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine | 131506-24-6

• 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-(carbobenzyloxy)-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine
• 英文别名: N-CBZ-L-Valyl-N-(2-indanyl)glycine；2-[2,3-dihydro-1H-inden-2-yl-[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]acetic acid
• CAS: 131506-24-6
• 化学式: C₂₄H₂₈N₂O₅
• 分子量: 424.497
• InChiKey: UQYOPQCFPRMZFD-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(carbobenzyloxy)-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine 在 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 生成 methyl N⁶-<4(S)-<amino>-2,2-difluoro-3-oxo-5-methylhexanoyl>-6-amino-2(S)-(aminoacetyl)hexanoate
  参考文献：
  名称：

  Inhibition of human leukocyte elastase by N-substituted peptides containing .alpha.,.alpha.-difluorostatone residues at P1

  摘要：

  A series of tripeptides which contain alpha,alpha-difluorostatone residues at P1-P1' and span the S3-S1' subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described contain the nonproteinogenic achiral residue N-(2,3-dihydro-1H-inden-2-yl)glycine at the P2-position. This residue has previously been shown in the case of HLE to be a good bioisosteric replacement for L-proline. Of the peptides prepared, those which contain the alpha,alpha-difluoromethylene keton derivative Of L-Valine (difluorostatone) are the preferred residue at the P1-primary specificity position. Substitution at P1 by the corresponding alpha,alpha-difluoromethylene ketones of L-leucine and L-phenylalanine gives inactive compounds. Of the tripeptides described the most potent in vitro compound is ethyl N-[N-CBZ-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycyl]-4(S)-amino-2,2-difluoro-3-oxo-5-methylhexanoate (17b) (IC50 = 0.635 muM). It is presumed that the inhibitor 17b interacts with the S3-S1' binding regions of HLE. Additionally extended binding inhibitors were prepared which interact with the S3-S3' binding subsites of HLE. In order to effect interaction with the S1'-S3' subsites of HLE, the leaving group side of cleaved peptides, spacers based upon Gly-Gly, and those linked via the N(epsilon) of L-lysine were utilized. One of the most potent extended compounds (P3-P3') in vitro is methyl N6-[4(S)-[[N-[N-CBZ-L-Valyl-N-(2,3-dihydro-1H-inden-2-yl)glycyl]amino]-2,2-difluoro-3-oxo-5-methylhexanoyl]-2(S)-(acetylamino)-6-aminohexanoate (24b) (IC50 = 0.057 muM). The described in vitro active inhibitors were also evaluated in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 22c, 5 min prior to HLE challenge (10 mug, it.) effectively inhibited hemorrhage (94.6%) in a dose-dependent manner. The described alpha,alpha-difluoromethylene ketone inhibitors are assumed to act as transition-state analogs. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing effect of the alpha,alpha-difluoromethylene functionality.

  DOI：

  10.1021/jm00104a004
• 作为产物：
  描述：

  CBZ-L-缬氨酸 在 4-二甲氨基吡啶 、 氢氧化钾 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 32.0h， 生成 N-(carbobenzyloxy)-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine
  参考文献：
  名称：

  Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones

  摘要：

  A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2-nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, alpha,alpha-dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4-[[[(4-chlorophenyl)sulfonyl]amino]carbonyl]phenyl]oxomethyl]-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]amide (20i; BI-RA-260) (IC50 = 0.084-mu-M). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8-mu-g. The inhibitor 20i, 20-mu-g administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200-mu-g of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20-mu-g it. 5 min prior to challenge with HLE.

  DOI：

  10.1021/jm00082a005

文献信息

• Imidazo[1,2-a]piperazines
  申请人：Boehringer Ingelheim Pharmaceuticals, Inc.

  公开号：US05166154A1

  公开（公告）日：1992-11-24

  Imidazo-[1,2-a]piperazines, inhibitors of human neutrophil elastase, having the following general structure ##STR1## wherein the substituents are defined hereinbelow, are disclosed.

  咪唑-[1,2-a]哌嗪类化合物，是人类中性粒细胞弹性蛋白酶的抑制剂，具有以下一般结构##STR1##其中取代基如下所定义。
• N-substituted amides
  申请人：BOEHRINGER INGELHEIM PHARMACEUTICALS INC.

  公开号：EP0369391A2

  公开（公告）日：1990-05-23

  Compounds of the formula are inhibitors of human leukocyte elastase.

  式中的化合物 是人类白细胞弹性蛋白酶的抑制剂。
• EP0863915B1
  申请人：——

  公开号：EP0863915B1

  公开（公告）日：2000-02-02
• US5166154A
  申请人：——

  公开号：US5166154A

  公开（公告）日：1992-11-24
• US5221665A
  申请人：——

  公开号：US5221665A

  公开（公告）日：1993-06-22