A-74273 | 130316-95-9

• 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: A-74273
• 英文别名: 5-{2-[1-Benzyl-2-(4-methoxymethoxy-piperidin-1-yl)-2-oxo-ethoxy]-hexanoylamino}-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid (3-morpholin-4-yl-propyl)-amide；(2S,4S,5S)-6-cyclohexyl-4-hydroxy-5-[[(2S)-2-[(2S)-1-[4-(methoxymethoxy)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]oxyhexanoyl]amino]-N-(3-morpholin-4-ylpropyl)-2-propan-2-ylhexanamide
• CAS: 130316-95-9
• 化学式: C₄₄H₇₄N₄O₈
• 分子量: 787.094
• InChiKey: NVMVSIUABPBQIL-LSLOANPCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  56
• 可旋转键数：
  24
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  A-74273 在 双氧水 作用下， 以 甲醇 为溶剂， 以55%的产率得到N-[3-(4-oxido-4-morpholinyl)propyl]-(2S,4S,5S,1'S,2'S)-5-[2-(1-{[4-(methoxymethoxy)piperidin-1-yl]carbonyl}-2-phenylethoxy)hexanamido]-6-cyclohexyl-4-hydroxy-2-isopropylhexanamide
  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
• 作为产物：
  描述：

  N-(3-氨丙基)吗啉 在 N-甲基吗啉 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 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 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 95.0h， 生成 A-74273
  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

• Pharmazeutische Kombination, die einen Hemmer des Renin-Angiotensin-Systems und einen Endothelin-Antagonisten enthält
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0634175A1

  公开（公告）日：1995-01-18

  Beschrieben werden pharmazeutische Kombinationspräparate, welche einen Hemmer des Renin-Angiotensin-Systems ("RAS-Hemmer") und einen Endothelin-Antagonisten enthalten. Diese Präparate eignen sich zur Bekämpfung bzw. Verhütung von Hypertension und deren Folgeerkrankungen sowie zur Behandlung von Herzinsuffizienz.

  本文描述了含有肾素-血管紧张素系统抑制剂（"RAS 抑制剂"）和内皮素拮抗剂的复方制剂。这些制剂适用于抗击或预防高血压及其继发疾病以及治疗心力衰竭。