(2S)-1-[(2S)-3-methyl-2-[(4-methylsulfanylbenzoyl)amino]butanoyl]-N-(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)pyrrolidine-2-carboxamide | 190387-96-3

• 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: (2S)-1-[(2S)-3-methyl-2-[(4-methylsulfanylbenzoyl)amino]butanoyl]-N-(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)pyrrolidine-2-carboxamide
• CAS: 190387-96-3
• 化学式: C₂₄H₃₄F₃N₃O₄S
• 分子量: 517.613
• InChiKey: OGWTVSNZDVDWGC-IQNGYNMSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  124
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S)-1-[(2S)-3-methyl-2-[(4-methylsulfanylbenzoyl)amino]butanoyl]-N-(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)pyrrolidine-2-carboxamide 在 碳酸氢钠 、 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以93%的产率得到(2S)-1-[(2S)-3-methyl-2-[(4-methylsulfonylbenzoyl)amino]butanoyl]-N-(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase

  摘要：

  Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protectin against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 mu g/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

  DOI：

  10.1021/jm960819g
• 作为产物：
  描述：

  4-甲硫基苯甲酸 、 (S)-1-((S)-2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-1-isopropyl-propyl)-amide 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以78%的产率得到(2S)-1-[(2S)-3-methyl-2-[(4-methylsulfanylbenzoyl)amino]butanoyl]-N-(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase

  摘要：

  Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protectin against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 mu g/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

  DOI：

  10.1021/jm960819g