1,1-dimethylethyl <1-<<<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>carbonyl>-3(S)-butenyl>carbamate | 137302-30-8

• 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: 1,1-dimethylethyl <1-<<<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>carbonyl>-3(S)-butenyl>carbamate
• 英文别名: 1,1-dimethylethyl (1-{[(1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-{[2-(4-morpholinyl)ethyl]amino}-4-oxobutyl)amino]carbonyl}-3(S)-butenyl)carbamate
• CAS: 137302-30-8
• 化学式: C₂₇H₄₆F₂N₄O₆
• 分子量: 560.682
• InChiKey: WRIAWHXHYMDZPN-FDFHNCONSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.36
• 重原子数：
  39.0
• 可旋转键数：
  13.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  129.23
• 氢给体数：
  4.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  1,1-dimethylethyl <1-<<<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>carbonyl>-3(S)-butenyl>carbamate 在 盐酸 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.25h， 生成 N-<(1,1-dimethylethoxy)carbonyl>-L-phenylalanyl-N-<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>-4,5-didehydro-L-norvalinamide
  参考文献：
  名称：

  Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors

  摘要：

  A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, Which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

  DOI：

  10.1021/jm00079a001
• 作为产物：
  描述：

  ethyl 4(S)-<(tert-butyloxycarbonyl)amino>-5-(cyclohexylmethyl)-2,2-difluoro-3(R)-hydroxypentanoate 在 盐酸 、 sodium hydroxide 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.0h， 生成 1,1-dimethylethyl <1-<<<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>carbonyl>-3(S)-butenyl>carbamate
  参考文献：
  名称：

  Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors

  摘要：

  A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, Which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

  DOI：

  10.1021/jm00079a001