N--L-phenylalanyl>-Nα-methyl-L-histidyl>-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl>-L-isoleucyl>(1-oxo-2-pyridyl)methylamine | 130985-46-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: N--L-phenylalanyl>-Nα-methyl-L-histidyl>-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl>-L-isoleucyl>(1-oxo-2-pyridyl)methylamine
• 英文别名: N-α--L-phenylalanyl>-N^α-methyl-L-histidyl>-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl>-L-isoleucyl>(1-oxo-2-pyridyl)methylamine
• CAS: 130985-46-5
• 化学式: C₅₃H₈₁N₉O₉
• 分子量: 988.281
• InChiKey: JUFNMFFXEDCQHU-LDVFFNKLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.51
• 重原子数：
  71.0
• 可旋转键数：
  24.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  242.1
• 氢给体数：
  6.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  N--L-phenylalanyl>-Nα-methyl-L-histidyl>-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl>-L-isoleucyl>(1-oxo-2-pyridyl)methylamine 、 三氟乙酸 以 二氯甲烷 为溶剂， 反应 1.0h， 以87%的产率得到N-α-(β-L-valyl)-L-phenylalanyl-N^α-methyl-L-histidyl>-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl>-L-isoleucyl>(1-oxo-2-pyridyl)methylamine tris(trifluoroacetate)
  参考文献：
  名称：

  Renin inhibitory peptides. Incorporation of polar, hydrophilic end groups into an active renin inhibitory peptide template and their evaluation in a human renin-infused rat model and in conscious sodium-depleted monkeys

  摘要：

  We previously reported that Boc-Pro-Phe-N-MeHis-Leu-psi[CHOHCH2]?? -Ile-Amp (1) is a potent and specific inhibitor of human renin in vitro. It was shown to resist degradation by selected proteases and a rat liver homogenate. It was shown to inhibit plasma renin activity and to reduce blood pressure in renin-dependent-animal models both by the intravenous and by the oral routes using dilute citric acid as vehicle. In an effort to discover compounds with improved pharmacological efficacy, we set out to modify the physical characteristics of this highly lipophilic renin inhibitor by incorporation of hydrophilic end groups. We report here a variety of water-solubilizing groups and the resulting structure-activity relationship of these compounds. They all maintain an extremely high level of enzyme inhibitory activity in vitro. Evaluation of these potent renin inhibitors in a human renin infused rat model suggests that some of these compounds exhibit improved pharmacological efficacy in vivo. This observation was further confirmed in the conscious sodium-depleted cynomolgus monkey. Importantly, the oral efficacy was demonstrated in a water vehicle in the absence of citric acid.

  DOI：

  10.1021/jm00106a026
• 作为产物：
  描述：

  3-(叔丁氧基羰基氨基)-3-甲基丁酸乙酯 在 氢氧化钾 、 氰基磷酸二乙酯 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 57.0h， 生成 N--L-phenylalanyl>-Nα-methyl-L-histidyl>-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanoyl>-L-isoleucyl>(1-oxo-2-pyridyl)methylamine
  参考文献：
  名称：

  Renin inhibitory peptides. Incorporation of polar, hydrophilic end groups into an active renin inhibitory peptide template and their evaluation in a human renin-infused rat model and in conscious sodium-depleted monkeys

  摘要：

  We previously reported that Boc-Pro-Phe-N-MeHis-Leu-psi[CHOHCH2]?? -Ile-Amp (1) is a potent and specific inhibitor of human renin in vitro. It was shown to resist degradation by selected proteases and a rat liver homogenate. It was shown to inhibit plasma renin activity and to reduce blood pressure in renin-dependent-animal models both by the intravenous and by the oral routes using dilute citric acid as vehicle. In an effort to discover compounds with improved pharmacological efficacy, we set out to modify the physical characteristics of this highly lipophilic renin inhibitor by incorporation of hydrophilic end groups. We report here a variety of water-solubilizing groups and the resulting structure-activity relationship of these compounds. They all maintain an extremely high level of enzyme inhibitory activity in vitro. Evaluation of these potent renin inhibitors in a human renin infused rat model suggests that some of these compounds exhibit improved pharmacological efficacy in vivo. This observation was further confirmed in the conscious sodium-depleted cynomolgus monkey. Importantly, the oral efficacy was demonstrated in a water vehicle in the absence of citric acid.

  DOI：

  10.1021/jm00106a026