N-<(1,1-dimethylethoxy)carbonyl>-L-alanyl-L-alanyl-N-<3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl>-L-prolinamide | 106771-20-4

• 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: N-<(1,1-dimethylethoxy)carbonyl>-L-alanyl-L-alanyl-N-<3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl>-L-prolinamide
• 英文别名: 1,1,1-Trifluoro-3[(N-tert-butyloxycarbonylalanyl)alanyl-prolylamino]-4-methylpentan-2-one；N-[(1,1-Dimethylethoxy)carbonyl]-L-alanyl-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide；tert-butyl N-[(2S)-1-oxo-1-[[(2S)-1-oxo-1-[(2S)-2-[(1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)carbamoyl]pyrrolidin-1-yl]propan-2-yl]amino]propan-2-yl]carbamate
• CAS: 106771-20-4
• 化学式: C₂₂H₃₅F₃N₄O₆
• 分子量: 508.538
• InChiKey: FFGHWNROQYNCDG-LOKSQKBWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  134
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-<(1,1-dimethylethoxy)carbonyl>-L-alanyl-L-alanyl-N-<3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl>-L-prolinamide 在 N-甲基吗啉 、 盐酸 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 3.5h， 生成 N-<<5-(dimethylamino)-1-naphtalenyl>sulfonyl>-L-alanyl-L-alanyl-N-<3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl>-L-prolinamide
  参考文献：
  名称：

  Synthesis of peptidyl fluoromethyl ketones and peptidyl .alpha.-keto esters as inhibitors of porcine pancreatic elastase, human neutrophil elastase, and rat and human neutrophil cathepsin G

  摘要：

  Comparison of MeO-Suc-Val-Pro-Phe-CO2Me (29) and MeO-Suc-Ala-Ala-Pro-Phe- CO2Me (25) with their corresponding trifluoromethyl ketones 9a and 9b, respectively, in rat and human neutrophil cathepsin G assays showed the alpha-keto esters to be more potent inhibitors. Likewise, Ac-Pro-Ala-Pro-Ala-CO2Me (21) was more potent than its corresponding trifluoromethyl ketone (9c) in both porcine pancreatic elastase and human neutrophil elastase assays. Within a set of Ala-Ala-Pro-Val-CF3 elastase inhibitors, the carbobenzyloxy (Cbz) N-protecting group conferred greater potency as a P5 site recognition unit for elastase than did dansyl, methoxysuccinyl, or tert-butyloxycarbonyl. Initial inhibition of elastase was greater when trifluoromethyl ketone 9f was added from a stock solution of dimethyl sulfoxide than when it had been buffer-equilibrated prior to assay, which suggests that the nonhydrated ketone is the more effective form of the inhibitor. The most potent elastase inhibitor we report is Na-(Ad-SO2)-N epsilon-(MeO-Suc)Lys-Pro-Val-CF3 (16) which has a Ki of 0.58 nM.

  DOI：

  10.1021/jm00163a063
• 作为产物：
  描述：

  N-(3,3,3-三氟-2-羟基-1-(甲基乙基)丙基)苯甲酰胺 在 N-甲基吗啉 、 盐酸 、 草酰氯 、 二甲基亚砜 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 24.25h， 生成 N-<(1,1-dimethylethoxy)carbonyl>-L-alanyl-L-alanyl-N-<3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl>-L-prolinamide
  参考文献：
  名称：

  Synthesis of peptidyl fluoromethyl ketones and peptidyl .alpha.-keto esters as inhibitors of porcine pancreatic elastase, human neutrophil elastase, and rat and human neutrophil cathepsin G

  摘要：

  Comparison of MeO-Suc-Val-Pro-Phe-CO2Me (29) and MeO-Suc-Ala-Ala-Pro-Phe- CO2Me (25) with their corresponding trifluoromethyl ketones 9a and 9b, respectively, in rat and human neutrophil cathepsin G assays showed the alpha-keto esters to be more potent inhibitors. Likewise, Ac-Pro-Ala-Pro-Ala-CO2Me (21) was more potent than its corresponding trifluoromethyl ketone (9c) in both porcine pancreatic elastase and human neutrophil elastase assays. Within a set of Ala-Ala-Pro-Val-CF3 elastase inhibitors, the carbobenzyloxy (Cbz) N-protecting group conferred greater potency as a P5 site recognition unit for elastase than did dansyl, methoxysuccinyl, or tert-butyloxycarbonyl. Initial inhibition of elastase was greater when trifluoromethyl ketone 9f was added from a stock solution of dimethyl sulfoxide than when it had been buffer-equilibrated prior to assay, which suggests that the nonhydrated ketone is the more effective form of the inhibitor. The most potent elastase inhibitor we report is Na-(Ad-SO2)-N epsilon-(MeO-Suc)Lys-Pro-Val-CF3 (16) which has a Ki of 0.58 nM.

  DOI：

  10.1021/jm00163a063

文献信息

• Peptidase inhibitors
  申请人：Merrell Pharmaceuticals Inc.

  公开号：US05496927A1

  公开（公告）日：1996-03-05

  This invention relates to analogs of peptidase substrates in which the amide group containing the scissile amide bond of the substrate peptide has been replaced by an activated electrophilic ketone moiety. These analogs of the peptidase substrates provide specific enzyme inhibitors for a variety of proteases, the inhibition of which will have useful physiological consequences in a variety of disease states.

  这项发明涉及肽酶底物的类似物，其中底物肽的含有可切割酰胺键的酰胺基团已被活化的亲电酮基团所取代。这些肽酶底物的类似物为各种蛋白酶提供特异性酶抑制剂，抑制这些蛋白酶将在各种疾病状态下产生有用的生理后果。
• Inhibition of Human Neutrophil Elastase. 3. An Orally Active Enol Acetate Prodrug
  作者：Joseph P. Burkhart、Jack R. Koehl、Shujaath Mehdi、Sherrie L. Durham、Michael J. Janusz、Edward W. Huber、Michael R. Angelastro、Shyam Sunder、William A. Metz

  DOI：10.1021/jm00002a003

  日期：1995.1

  vitro studies, in the presence of added esterase, and 19F NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo. The ED50 value for (E)-N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[2- (acetyloxy)-3,3,4,4,4-pentafluoro-1-(1-methylethyl)-1-buteny l]-L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg

  N- [4-（4-吗啉基羰基）苯甲酰基] -L-戊基-N- [3,3,4,4,4-戊五氟-1-（1-甲基乙基）-2-氧丁基] -L的几种类似物合成了其中已消除了P1残基手性中心的β-脯氨酰胺（1），并作为人嗜中性粒细胞弹性蛋白酶（HNE）的抑制剂进行了测试。在这项工作的过程中观察到的结果导致开发了一种从HNE抑制剂（在P1处含有差向异构体的混合物）一步一步，立体选择性地合成E-烯醇乙酸酯衍生物的方法。在存在酯酶的情况下进行的体外研究以及在生物介质中的19 F NMR研究表明，乙酸烯醇酯衍生物应在体内充当前药。（E）-N- [4-（4-吗啉基羰基）苯甲酰基] -L-戊基-N- [2-（乙酰氧基）-3,3,4,4,4-五氟-1-（1）的ED50值-甲基乙基）-1-丁烯基1] -L-脯氨酰胺（20），
• Solid-Phase Synthesis of Peptidyl Trifluoromethyl Ketones
  作者：Marc-André Poupart、Gulrez Fazal、Sylvie Goulet、Ly Thy Mar

  DOI：10.1021/jo9815204

  日期：1999.2.1
• PEET, NORTON P.;BURKHART, JOSEPH P.;ANGELASTRO, MICHAEL R.;GIROUX, EUGENE+, J. MED. CHEM., 33,(1990) N, C. 394-407
  作者：PEET, NORTON P.、BURKHART, JOSEPH P.、ANGELASTRO, MICHAEL R.、GIROUX, EUGENE+

  DOI：——

  日期：——
• Novel peptidase inhibitors
  申请人：MERRELL DOW PHARMACEUTICALS INC.

  公开号：EP0195212B1

  公开（公告）日：1993-11-24