methyl (2S,3S)-3-methyl-2-[[(2S,3S)-3-methyl-2-(phenylmethoxycarbonylamino)pentyl]amino]pentanoate | 1027036-48-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl (2S,3S)-3-methyl-2-[[(2S,3S)-3-methyl-2-(phenylmethoxycarbonylamino)pentyl]amino]pentanoate
• CAS: 1027036-48-1
• 化学式: C₂₁H₃₄N₂O₄
• 分子量: 378.512
• InChiKey: XPAPDGZZNQKBKX-DKKFBQAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  27
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  76.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (2S,3S)-3-methyl-2-[[(2S,3S)-3-methyl-2-(phenylmethoxycarbonylamino)pentyl]amino]pentanoate 在 lithium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 96.0h， 以74%的产率得到(2S,3S)-3-methyl-2-[[(2S,3S)-3-methyl-2-(phenylmethoxycarbonylamino)pentyl]amino]pentanoic acid
  参考文献：
  名称：

  Design of a Potent Combined Pseudopeptide Endothelin-A/Endothelin-B Receptor Antagonist, Ac-dBhg¹⁶-Leu-Asp-Ile-[NMe]Ile-Trp²¹ (PD 156252):  Examination of Its Pharmacokinetic and Spectral Properties

  摘要：

  The endothelins (ETs) are a family of bicyclic 21-amino acid peptides that are potent and prolonged vasoconstrictors. It has been shown that highly potent combined ETA/ETB receptor antagonists can be developed from the C-terminal hexapeptide of ET (His(16)-Leu(17)-Asp(18)-Ile(19)-Ile(20)-Trp(21)), such as Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142893) and Ac-DBhg(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 145065). However, these compounds are relatively unstable to enzymatic proteolysis as determined in an in vitro rat intestinal perfusate assay. This instability is thought to be due to carboxypeptidase activity. In fact, incubation of PD 145065 with carboxypeptidase inhibitors greatly increased its half-life in rat intestinal perfusate. By performing a reduced amide bond and N-methyl amino acid scan, it was discovered that N-methylation of Ile(20) resulted in a compound (Ac-DBhg(16)-Leu-Asp-Ile-[NMe]Ile-Trp(21), PD 156252) that retained full receptor affinity at both endothelin receptor subtypes along with enhanced proteolytic stability and cellular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters the preferred structure of the entire molecule and may be responsible for the observed enhanced metabolic stability.

  DOI：

  10.1021/jm970161m
• 作为产物：
  描述：

  N-苄氧羰基-L-异亮氨酸 在 lithium aluminium tetrahydride 、 sodium cyanoborohydride 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 methyl (2S,3S)-3-methyl-2-[[(2S,3S)-3-methyl-2-(phenylmethoxycarbonylamino)pentyl]amino]pentanoate
  参考文献：
  名称：

  Design of a Potent Combined Pseudopeptide Endothelin-A/Endothelin-B Receptor Antagonist, Ac-dBhg¹⁶-Leu-Asp-Ile-[NMe]Ile-Trp²¹ (PD 156252):  Examination of Its Pharmacokinetic and Spectral Properties

  摘要：

  The endothelins (ETs) are a family of bicyclic 21-amino acid peptides that are potent and prolonged vasoconstrictors. It has been shown that highly potent combined ETA/ETB receptor antagonists can be developed from the C-terminal hexapeptide of ET (His(16)-Leu(17)-Asp(18)-Ile(19)-Ile(20)-Trp(21)), such as Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142893) and Ac-DBhg(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 145065). However, these compounds are relatively unstable to enzymatic proteolysis as determined in an in vitro rat intestinal perfusate assay. This instability is thought to be due to carboxypeptidase activity. In fact, incubation of PD 145065 with carboxypeptidase inhibitors greatly increased its half-life in rat intestinal perfusate. By performing a reduced amide bond and N-methyl amino acid scan, it was discovered that N-methylation of Ile(20) resulted in a compound (Ac-DBhg(16)-Leu-Asp-Ile-[NMe]Ile-Trp(21), PD 156252) that retained full receptor affinity at both endothelin receptor subtypes along with enhanced proteolytic stability and cellular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters the preferred structure of the entire molecule and may be responsible for the observed enhanced metabolic stability.

  DOI：

  10.1021/jm970161m

文献信息

• Design of a Potent Combined Pseudopeptide Endothelin-A/Endothelin-B Receptor Antagonist, Ac-<scp>d</scp>Bhg¹⁶-Leu-Asp-Ile-[NMe]Ile-Trp²¹ (PD 156252):  Examination of Its Pharmacokinetic and Spectral Properties
  作者：Wayne L. Cody、John X. He、Michael D. Reily、Stephen J. Haleen、Donnelle M. Walker、Eric L. Reyner、Barbra H. Stewart、Annette M. Doherty

  DOI：10.1021/jm970161m

  日期：1997.7.1

  The endothelins (ETs) are a family of bicyclic 21-amino acid peptides that are potent and prolonged vasoconstrictors. It has been shown that highly potent combined ETA/ETB receptor antagonists can be developed from the C-terminal hexapeptide of ET (His(16)-Leu(17)-Asp(18)-Ile(19)-Ile(20)-Trp(21)), such as Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142893) and Ac-DBhg(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 145065). However, these compounds are relatively unstable to enzymatic proteolysis as determined in an in vitro rat intestinal perfusate assay. This instability is thought to be due to carboxypeptidase activity. In fact, incubation of PD 145065 with carboxypeptidase inhibitors greatly increased its half-life in rat intestinal perfusate. By performing a reduced amide bond and N-methyl amino acid scan, it was discovered that N-methylation of Ile(20) resulted in a compound (Ac-DBhg(16)-Leu-Asp-Ile-[NMe]Ile-Trp(21), PD 156252) that retained full receptor affinity at both endothelin receptor subtypes along with enhanced proteolytic stability and cellular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters the preferred structure of the entire molecule and may be responsible for the observed enhanced metabolic stability.