Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents
Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents
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DOI：
10.1021/jm2011673
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发表时间：
2011-12-22
影响因子：
7.3
通讯作者：
Chamberlain, Stanley
中科院分区：
文献类型：
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作者：
McGuigan, Christopher;Madela, Karolina;Chamberlain, Stanley
我们在此报告二氨基磷酸酯作为一个重要的新的磷酸盐前药基序。报道了两个6-O-烷基2 '-C-甲基鸟苷的67个二氨基磷酸酯，其二酰胺酯结构有显著变化。报道了对称和不对称的二氨基磷酸酯，其衍生自各种酯化的氨基酸，D和L，也可以由各种简单的胺形成。在复制子测定中评价所有化合物相对于丙型肝炎病毒的活性，并观察纳摩尔活性水平。许多化合物在100 μ M时无细胞毒性，导致高抗病毒选择性。所述试剂在酸性、中性和中等碱性培养基中以及在选定的生物培养基中是稳定的，但显示出被羧肽酶有效加工并在细胞中有效产生游离核苷一磷酸。根据体外数据，选择了8根电极导线进行额外的体内评价，目的是选择一种候选电极导线进行临床研究。这种磷酰胺酯前药方法可能在HCV和抗病毒药之外具有广泛的应用，因为它提供了磷酰胺酯前药的许多优点，但没有大多数情况下存在的手性问题。
We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both D and L., and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 mu M, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases.