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首页> 外文期刊>Journal of pharmaceutical sciences. >Structural features determining the intestinal epithelial permeability and efflux of novel HIV-1 protease inhibitors.
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Structural features determining the intestinal epithelial permeability and efflux of novel HIV-1 protease inhibitors.

机译：结构特征决定了新型HIV-1蛋白酶抑制剂的肠上皮通透性和流出。

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The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R(1) and R(2) ) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R(1) substituents and a small (bromo-) R(2) substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R(1) position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties.
机译：这项研究的主要目的是确定改变一系列新型HIV-1蛋白酶抑制剂（PIs）的肠上皮通透性和外排的结构特征。选择了11个在过渡态模拟支架中含有叔醇的PI，其中两个取代基（R（1）和R（2））有系统地变化。选择茚地那韦作为参考化合物。在2/4 / A1和Caco-2单层中研究了顶至基底外侧的通透性。此外，在Caco-2单层中研究了基底外侧到顶部的渗透性，并计算了流出比。 2/4 / A1细胞中没有活性药物转运过程，因此可以识别和建模影响被动渗透性的结构元素。例如，小的芳族R（1）取代基和小的（Bromo-）R（2）取代基具有较高的被动渗透性。在Caco-2细胞中进行外排研究表明，酰胺取代的中性疏水氨基酸（例如缬氨酸和亮氨酸）位于R（1）位置，减少了根尖到基底外侧的转运并增强了外排。我们得出的结论是，我们的研究揭示了一系列PI改变了肠上皮通透性和外排的结构特征，并希望这些结果能够有助于通透性提高和外排特性有限的PI的合成。

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