(2S)-2-[[(3S,4S)-5-cyclohexyl-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]-4-methylpentanoic acid | 128972-24-7

• 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: (2S)-2-[[(3S,4S)-5-cyclohexyl-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]-4-methylpentanoic acid
• CAS: 128972-24-7
• 化学式: C₂₂H₄₀N₂O₆
• 分子量: 428.569
• InChiKey: JRYUGXQGAKLEMO-BZSNNMDCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.22
• 重原子数：
  30.0
• 可旋转键数：
  10.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  124.96
• 氢给体数：
  4.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (2S)-2-[[(3S,4S)-5-cyclohexyl-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]-4-methylpentanoic acid 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 (2S)-2-[[(3S,4S)-5-cyclohexyl-3-hydroxy-4-[[2-[8-(2-methylpropyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]acetyl]amino]pentanoyl]amino]-4-methyl-N-(pyridin-2-ylmethyl)pentanamide
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives

  摘要：

  A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.

  DOI：

  10.1021/jm00171a005
• 作为产物：
  描述：

  5-环己基-2,4,5-三脱氧-4-[[(1,1-二甲基乙氧基)羰基]氨基]-L-苏-戊糖酸 在 sodium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 乙醇 为溶剂， 反应 19.5h， 生成 (2S)-2-[[(3S,4S)-5-cyclohexyl-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]-4-methylpentanoic acid
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives

  摘要：

  A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.

  DOI：

  10.1021/jm00171a005

文献信息

• ROBERTS, DAVID A.;BRADBURY, ROBERT H.;BROWN, DAVID;FAULL, ALAN;GRIFFITHS,+, J. MED. CHEM., 33,(1990) N, C. 2326-2334
  作者：ROBERTS, DAVID A.、BRADBURY, ROBERT H.、BROWN, DAVID、FAULL, ALAN、GRIFFITHS,+

  DOI：——

  日期：——