Serine peptide phosphoester prodrugs of cyclic cidofovir: Synthesis, transport, and antiviral activity
Serine peptide phosphoester prodrugs of cyclic cidofovir: Synthesis, transport, and antiviral activity
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DOI：
10.1021/mp8000099
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发表时间：
2008-07-01
影响因子：
4.9
通讯作者：
McKenna, Charles E.
中科院分区：
文献类型：
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作者：
Eriksson, Ulrika;Peterson, Larryn W.;McKenna, Charles E.
西多福韦 (HPMPC, 1) 是一种广谱抗病毒药物，目前用于治疗艾滋病相关的人巨细胞病毒 (HCMV) 视网膜炎，并具有公认的治疗正痘病毒感染的潜力，但因其口服生物利用度较低而受到限制。与 1 相比，环状西多福韦 (2) 的肾毒性降低，同时还表现出有效的抗病毒活性。在这里，我们详细描述了四种 cHPMPC 二肽缀合物的前药合成和评估，其中 2 的游离 POH 被 X-L-Ser(OMe) 二肽的 Ser 侧链醇基酯化：3 (X = L-Ala)、4 (X = L-Val)、5 (X = L-Leu) 和 6 (X = L-Phe)。大鼠灌注研究表明，在体内鼠模型中，4 的肠系膜通透性比 1 大 20 倍以上，并且 4 的生物利用度相对于 1 增加了 6 倍。在胃肠道和肝脏匀浆中，cHFMPC 前药迅速水解为 2。前药 3、4 和 5 在 HFF 和 KB 细胞中在 100 μM 时无毒，在基于细胞的空斑减少测定中，HCMV 的 IC50 值为 0.1-0.5 μM，两种正痘病毒（牛痘和牛痘）的 IC50 值为 10 μM。通过掺入生物良性二肽部分而赋予 3-6 增强的转运特性，以及 Ser-O-P 连接的轻松裂解表明这些前药代表了增强 2 生物利用度的有前途的新方法。
Cidofovir (HPMPC, 1), a broad-spectrum antiviral agent, is currently used to treat AIDS-related human cytomegalovirus (HCMV) retinitis and has recognized therapeutic potential for orthopox virus infections, but is limited by its low oral bioavailability. Cyclic cidofovir (2) displays decreased nephrotoxicity compared to 1, while also exhibiting potent antiviral activity. Here we describe in detail the synthesis and evaluation as prodrugs of four cHPMPC dipeptide conjugates in which the free POH of 2 is esterified by the Ser side chain alcohol group of an X-L-Ser(OMe) dipeptide: 3 (X = L-Ala), 4 (X = L-Val), 5 (X = L-Leu), and 6 (X = L-Phe). Perfusion studies in the rat establish that the mesenteric permeability to 4 is more than 20-fold greater than to 1, and the bioavailability of 4 is increased 6-fold relative to 1 in an in vivo murine model. In gastrointestinal and liver homogenates, the cHFMPC prodrugs are rapidly hydrolyzed to 2. Prodrugs 3, 4, and 5 are nontoxic at 100 mu M in HFF and KB cells and in cell-based plaque reduction assays had IC50 values of 0.1-0.5 mu M for HCMV and 10 mu M for two orthopox viruses (vaccinia and cowpox). The enhanced transport properties of 3-6, conferred by incorporation of a biologically benign dipeptide moiety, and the facile cleavage of the Ser-O-P linkage suggest that these prodrugs represent a promising new approach to enhancing the bioavailability of 2.