(2S)-3-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]hexoxy]phenyl]-2-(3-phenylpropanoylamino)propanoic acid | 142355-89-3

• 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: (2S)-3-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]hexoxy]phenyl]-2-(3-phenylpropanoylamino)propanoic acid
• CAS: 142355-89-3
• 化学式: C₂₉H₄₀N₂O₆
• 分子量: 512.646
• InChiKey: RJHRCEXZTJIMDS-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  37
• 可旋转键数：
  17
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S)-3-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]hexoxy]phenyl]-2-(3-phenylpropanoylamino)propanoic acid 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 以82%的产率得到2-(S)-<(phenethylcarbonyl)amino>-3-<4-<(6-aminohexyl)oxy>phenyl>propionic acid hydrochloride
  参考文献：
  名称：

  Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp

  摘要：

  Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation. Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of > 24 000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with iv infusions of 0.1-10 mu g/kg/min of 23m in anesthetized dogs, with 10 mu g/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infusions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.

  DOI：

  10.1021/jm00042a007
• 作为产物：
  描述：

  N-(6-羟基己基)氨基甲酸叔丁酯 在 palladium on activated charcoal sodium hydroxide 、 四溴化碳 、 氢气 、 sodium hydride 、 sodium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 水 、 乙腈 为溶剂， 反应 62.5h， 生成 (2S)-3-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]hexoxy]phenyl]-2-(3-phenylpropanoylamino)propanoic acid
  参考文献：
  名称：

  Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp

  摘要：

  Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation. Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of > 24 000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with iv infusions of 0.1-10 mu g/kg/min of 23m in anesthetized dogs, with 10 mu g/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infusions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.

  DOI：

  10.1021/jm00042a007

文献信息

• Synthesis and Evaluation of Novel Coumarin-Based Esterase-Sensitive Cyclic Prodrugs of Peptidomimetic RGD Analogs with Improved Membrane Permeability.
  作者：Binghe WANG、Wei WANG、Gian P. CAMENISCH、Jennifer ELMO、Huijuan ZHANG、Ronald T. BORCHARDT

  DOI：10.1248/cpb.47.90

  日期：——

  Earlier, we reported the development of a coumarin-based prodrug system that could be used for the preparation of cyclic prodrugs of opioid peptides. These cyclic prodrugs exhibited excellent membrane permeability characteristics. Therefore, it was of interest to determine the effects of this prodrug strategy on the membrane permeabilities of peptidomimetics which also have low membrane permeabilities. For this study, we have chosen two RGD (Arg-Gly-Asp) peptidomimetics, which have the potentials to be developed clinically as orally active antithrombotic agents. However, the clinical development of oral dosage forms of these RGD analogs has been hindered by their low intestinal mucosal permeability. Therefore, we have synthesized the corresponding coumarin-based cyclic prodrugs of these RGD peptidomimetics, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. These cyclic prodrugs were shown to have higher membrane interaction potentials, as estimated by their partitioning between aqueous buffer and an immobilized artificial membrane, than the corresponding RGD analogs suggesting that they should exhibit good membrane permeation characteristics. Subsequently, in a separate study these cyclic prodrugs were shown to be 5 to 6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier, than the corresponding RGD peptidomimetics.

  早些时候，我们报道了香豆素原药体系的开发，该体系可用于制备阿片肽的环状原药。这些环状原药具有出色的膜渗透特性。因此，我们有兴趣确定这种原药策略对膜渗透性较低的拟肽类药物膜渗透性的影响。在这项研究中，我们选择了两种 RGD（Arg-Gly-Asp）拟肽物，它们具有作为口服活性抗血栓药物进行临床开发的潜力。然而，由于这些 RGD 类似物的肠粘膜渗透性较低，其口服剂型的临床开发一直受到阻碍。因此，我们合成了这些 RGD 肽拟类似物的相应香豆素基环状原药，其两个极性最强的官能团（羧基和氨基）分别被掩蔽为酯和酰胺。根据这些环状原药在水缓冲液和固定人工膜之间的分配估计，它们比相应的 RGD 类似物具有更高的膜相互作用电位，这表明它们应该具有良好的膜渗透特性。随后，在另一项研究中，这些环状原药渗透 Caco-2 细胞单层（一种肠粘膜屏障的体外细胞培养模型）的能力比相应的 RGD 肽模拟物强 5 到 6 倍。
• Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp
  作者：Melissa S. Egbertson、Charles T.-C. Chang、Mark E. Duggan、Robert J. Gould、Wasyl Halczenko、George D. Hartman、William L. Laswell、Joseph J. Lynch、Robert J. Lynch

  DOI：10.1021/jm00042a007

  日期：1994.8

  Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation. Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of > 24 000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with iv infusions of 0.1-10 mu g/kg/min of 23m in anesthetized dogs, with 10 mu g/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infusions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.