Khandazhinskaya A, Yasko M, Shirokova E
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, ul. Vavilova 32, Moscow 119991, Russia.
Curr Med Chem. 2006;13(24):2953-80. doi: 10.2174/092986706778521896.
Acyclic nucleoside analogues bearing phosphonomethoxy residues in the side chain (ANP) attract much attention due to a very beneficial combination of biological properties. Intensive work of organic chemists during the last two decades resulted in a large panel of new compounds that were evaluated as potential antiviral drugs. Herein, we present an overview of major chemical structures within the group of acyclic nucleoside analogues containing phosphonomethoxy side fragments and describe main aspects of their synthesis and antiviral potential. We also describe progress in "prodrug" approaches applied to this chemical group to improve pharmacokinetic profiles of the potential candidates. Chemical modifications in the molecule of parental ANP aimed at blocking of phosphonate charges resulted in a set of promising derivatives, two of which have been recently approved for treatment of hepatits B (Hepsera) and HIV (Viread). The preparation, antiviral properties and some aspects of metabolic transformations and pharmacokinetics of ANP prodrugs are discussed.
侧链带有膦酰甲氧基残基的无环核苷类似物(ANP)因其多种有益生物学特性的良好组合而备受关注。过去二十年间有机化学家的大量工作产生了一大批新化合物,这些化合物被评估为潜在的抗病毒药物。在此,我们概述了含有膦酰甲氧基侧链片段的无环核苷类似物组内的主要化学结构,并描述了它们的合成及抗病毒潜力的主要方面。我们还描述了应用于该化学组以改善潜在候选药物药代动力学特征的“前药”方法的进展。旨在阻断膦酸酯电荷的母体ANP分子的化学修饰产生了一系列有前景的衍生物,其中两种最近已被批准用于治疗乙型肝炎(替诺福韦)和艾滋病病毒(富马酸替诺福韦二吡呋酯)。本文讨论了ANP前药的制备、抗病毒特性以及代谢转化和药代动力学的一些方面。