Synthesis and evaluation of novel coumarin-based esterase-sensitive cyclic prodrugs of peptidomimetic RGD analogs with improved membrane permeability.
Synthesis and evaluation of novel coumarin-based esterase-sensitive cyclic prodrugs of peptidomimetic RGD analogs with improved membrane permeability.
复制标题
具有改善膜渗透性的新型香豆素基酯酶敏感的拟肽 RGD 类似物环状前药的合成和评估。
DOI：
10.1248/cpb.47.90
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发表时间：
1999
影响因子：
1.7
通讯作者：
Ronald T. Borchardt
中科院分区：
文献类型：
--
作者：
Binghe Wang;Wei Wang;Gian P. Camenisch;J. Elmo;Huijuan Zhang;Ronald T. Borchardt
早些时候，我们报道了一种基于香豆素的前药系统的开发，该系统可用于制备阿片肽的环状前药。这些环状前药表现出优异的膜渗透性特征。因此，确定这种前药策略对也具有低膜渗透性的肽模拟物的膜渗透性的影响是有意义的。在这项研究中，我们选择了两个RGD（Arg-Gly-Asp）肽模拟物，这有可能被开发为口服活性抗血栓药物临床。然而，这些RGD类似物的口服剂型的临床开发受到其低肠粘膜渗透性的阻碍。因此，我们已经合成了这些RGD肽模拟物的相应的基于香豆素的环状前药，其具有两个最极性的官能团，羧基和氨基，分别被掩蔽为酯和酰胺。这些环状前药被证明具有更高的膜相互作用的潜力，估计它们之间的水性缓冲液和固定的人工膜的分区，比相应的RGD类似物，这表明它们应该表现出良好的膜渗透特性。随后，在一项单独的研究中，这些环状前药显示出比相应的RGD肽模拟物渗透Caco-2细胞单层（肠粘膜屏障的体外细胞培养模型）的能力高5至6倍。
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.