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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Thiodipeptides targeting the intestinal oligopeptide transporter as a general approach to improving oral drug delivery
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Thiodipeptides targeting the intestinal oligopeptide transporter as a general approach to improving oral drug delivery

机译：靶向肠道寡肽转运蛋白作为改善口服药物递送的一般方法

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The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of research into drug delivery. Whilst the substrate capacity of this transporter is broad, studies have largely been limited to small peptides and peptide-like drugs. Here, we demonstrate for the first time that a diverse range of drugs can be targeted towards transport by PepT1 using a hydrolysis resistant carrier. Eleven prodrugs were synthesized by conjugating modified dipeptides containing a thioamide bond to the approved drugs ibuprofen, gabapentin, propofol, aspirin, acyclovir, nabumetone, atenolol, zanamivir, baclofen and mycophenolate. Except for the aspirin and acyclovir prodrugs, which were unstable in the assay conditions and were not further studied, the prodrugs were tested for affinity and transport by PepT1 expressed inXenopus laevisoocytes: binding affinities ranged from approximately 0.1 to 2?mM. Compounds which showed robust transport in an oocytetrans-stimulation assay were then tested for transcellular transport in Caco-2?cell monolayers: all five tested prodrugs showed significant PepT1-mediated transcellular uptake. Finally, the ibuprofen and propofol prodrugs were tested for absorption in rats: following oral dosing the intact prodrugs and free ibuprofen were measured in the plasma. This provides proof-of-concept for the idea of targeting poorly bioavailable drugs towards PepT1 transport as a general means of improving oral permeability.
机译：肠道寡肽转运蛋白，PEPT1的广泛的底物的能力，使得有研究的一个关键目标到药物递送。虽然这转运蛋白的底物的能力是广泛的，研究已经在很大程度上被局限于小肽和肽类药物。在这里，我们表现出的第一次的药物多种多样，可以向运输通过PEPT1使用耐水解性载体的针对性。十一前药通过缀合含有硫代酰胺键与布洛芬批准的药物，加巴喷丁，丙泊酚，阿司匹林，阿昔洛韦，萘丁美酮，阿替洛尔，扎那米韦改性二肽合成，巴氯芬和霉。除阿司匹林和阿昔洛韦的前药，这是在该测定条件下不稳定，并没有进一步研究，前药被用于通过PEPT1亲和力和运输测试表达inXenopus laevisoocytes：结合亲和力为约0.1至2mm范围内。化合物，其显示出在oocytetrans-刺激测定强大的传输然后用于跨细胞转运中的Caco-2测试的细胞单层：所有五个测试的前药表现出显著PEPT1介导的跨细胞摄取。最后，布洛芬和丙泊酚前药被用于吸收在大鼠中测试：口服给药后的完整前体药物和血浆中，测定游离布洛芬。这提供了验证的概念对PEPT1交通改善口腔渗透性的一般手段针对的生物利用度差的药物的想法。

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