(2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[(2RS)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)propionamido]hexanamide | 128901-36-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[(2RS)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)propionamido]hexanamide
• 英文别名: (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-propan-2-yl-5-[[2-(8-propyl-6-pyridin-3-yl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-pyridin-3-ylpropanoyl]amino]hexanamide
• CAS: 128901-36-0；128948-62-9；130321-33-4
• 化学式: C₄₀H₅₆N₈O₃
• 分子量: 696.936
• InChiKey: LGPIXWBRAXFATQ-JENCEGNZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  51
• 可旋转键数：
  18
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  147
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  异戊酸 在 palladium on activated charcoal 六甲基磷酰三胺 、 ammonium formate 、 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 、 lithium diisopropyl amide 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[(2RS)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)propionamido]hexanamide
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives

  摘要：

  A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

  DOI：

  10.1021/jm00171a006

文献信息

• 5-(heterocyclylalkanoyl)amino-4-hydroxypentanamides
  申请人：Imperial Chemical Industries plc

  公开号：US05091425A1

  公开（公告）日：1992-02-25

  This invention concerns novel nitrogen derivatives of the formula I ##STR1## (and their pharmaceutically-acceptable salts), together with pharmaceutical compositions containing them. The nitrogen derivatives are inhibitors of the catalytic action of renin. The invention further concerns novel processes for the manufacture of said inhibitors.

  本发明涉及公式I的新型氮衍生物（及其药学上可接受的盐），以及含有它们的药物组合物。这些氮衍生物是肾素催化作用的抑制剂。本发明还涉及制造该抑制剂的新型方法。
• 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。
• Heterocyclic amides
  申请人：ZENECA LIMITED

  公开号：EP0369743B1

  公开（公告）日：1995-04-19
• US5091425A
  申请人：——

  公开号：US5091425A

  公开（公告）日：1992-02-25
• 1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives
  作者：Robert H. Bradbury、John S. Major、Alec A. Oldham、Janet E. Rivett、David A. Roberts、Anthony M. Slater、David Timms、David Waterson

  DOI：10.1021/jm00171a006

  日期：1990.9

  A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.