(4-{2-[1-Benzyl-2-(4-methoxymethoxy-piperidin-1-yl)-2-oxo-ethoxy]-hexanoylamino}-5-cyclohexyl-3-hydroxy-1-isopropyl-pentyl)-carbamic acid 2-pyrrolidin-1-yl-ethyl ester | 140660-74-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (4-{2-[1-Benzyl-2-(4-methoxymethoxy-piperidin-1-yl)-2-oxo-ethoxy]-hexanoylamino}-5-cyclohexyl-3-hydroxy-1-isopropyl-pentyl)-carbamic acid 2-pyrrolidin-1-yl-ethyl ester
• 英文别名: 2-pyrrolidin-1-ylethyl N-[(3S,5S,6S)-7-cyclohexyl-5-hydroxy-6-[[(2S)-2-[(2S)-1-[4-(methoxymethoxy)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]oxyhexanoyl]amino]-2-methylheptan-3-yl]carbamate
• CAS: 140660-74-8
• 化学式: C₄₃H₇₂N₄O₈
• 分子量: 773.067
• InChiKey: JPETZYJYAGYUKG-HECCNADXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  55
• 可旋转键数：
  24
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  N-(2-羟乙基)-吡咯烷 在 N-甲基吗啉 、 二苯基膦叠氮化物 、 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 、 三乙胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 115.0h， 生成 (4-{2-[1-Benzyl-2-(4-methoxymethoxy-piperidin-1-yl)-2-oxo-ethoxy]-hexanoylamino}-5-cyclohexyl-3-hydroxy-1-isopropyl-pentyl)-carbamic acid 2-pyrrolidin-1-yl-ethyl ester
  参考文献：
  名称：

  C-Terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties

  摘要：

  We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.

  DOI：

  10.1021/jm00088a007

文献信息

• C-Terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties
  作者：Steven A. Boyd、Anthony K. L. Fung、William R. Baker、Robert A. Mantei、Yoek Lin Armiger、Herman H. Stein、Jerome Cohen、David A. Egan、Jennifer L. Barlow

  DOI：10.1021/jm00088a007

  日期：1992.5

  We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.