Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art.
Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art.
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循环核苷磷酸盐的烷氧基烷基前药增强了口服抗病毒活性并降低毒性：当前的抗病毒活性。
DOI：
10.1016/j.antiviral.2009.01.005
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发表时间：
2009-05
影响因子：
7.6
通讯作者：
Hostetler, Karl Y.
中科院分区：
文献类型：
--
作者：
Hostetler, Karl Y.
关键词：
尽管无环核苷膦酸酯西多福韦、阿德福韦和替诺福韦分别被批准用于治疗人巨细胞病毒、肝炎B和HIV感染，但它们的效用受到口服生物利用度低、肾毒性和细胞渗透性差的限制。过去十年的研究表明，这些不良特征可以通过用烷氧基烷基取代化合物来消除，实际上将它们伪装成溶血磷脂。在这种修饰形式中，药物容易在胃肠道中被吸收，并且在血浆中具有延长的循环时间。活性代谢物在细胞内的半衰期也很长，因此可以不频繁给药。由于这些修饰药物不被导致非环核苷膦酸酯在肾小管细胞中蓄积的转运机制识别，因此它们没有肾毒性。烷氧基烷基酯化还通过改善无环核苷膦酸酯向细胞中的递送而显著增加其体外抗病毒活性。例如，环西多福韦的烷氧基烷基酯（一种溶解性较低的化合物）在单次玻璃体内注射后保持抗病毒活性3个月。这些新化合物中的两种，十六烷氧基丙基-西多福韦（CMX-001）和十六烷氧基丙基-替诺福韦（CMX-157）目前正在临床开发中。本文重点介绍了西多福韦和（S）-HPMPA的十六烷氧基丙基酯和十八烷氧基乙基酯，描述了它们的合成以及对一系列正痘病毒、疱疹病毒、腺病毒和其他双链DNA病毒的体外和体内活性的评价。突出了对其他核苷膦酸酯抗病毒药物的扩展，表明这种新方法可以显着改善这些药物的药用特性。
Although the acyclic nucleoside phosphonates cidofovir, adefovir and tenofovir are approved for treating human cytomegalovirus, hepatitis B and HIV infections, respectively, their utility is limited by low oral bioavailability, renal toxicity and poor cell penetration. Research over the past decade has shown that these undesirable features can be eliminated by esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids. In this modified form, the drugs are readily taken up in the gastrointestinal tract and have a prolonged circulation time in plasma. The active metabolite also has a long half life within cells, permitting infrequent dosing. Because these modified drugs are not recognized by the transport mechanisms that cause the accumulation of acyclic nucleoside phosphonates in renal tubular cells, they lack nephrotoxicity. Alkoxyalkyl esterification also markedly increases the in vitro antiviral activity of acyclic nucleoside phosphonates by improving their delivery into cells. For example, an alkoxyalkyl ester of cyclic-cidofovir, a less soluble compound, retains antiviral activity for 3 months following a single intravitreal injection. Two of these novel compounds, hexadecyloxypropyl-cidofovir (CMX-001) and hexadecyloxypropyl-tenofovir (CMX-157) are now in clinical development. This article focuses on the hexadecyloxypropyl and octadecyloxyethyl esters of cidofovir and (S)-HPMPA, describing their synthesis and the evaluation of their in vitro and in vivo activity against a range of orthopoxviruses, herpesviruses, adenoviruses and other double-stranded DNA viruses. The extension to other nucleoside phosphonate antivirals is highlighted, demonstrating that this novel approach can markedly improve the medicinal properties of these drugs.
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影响因子：
7.6
作者：
Dal Pozzo, Fabiana;Andrei, Graciela;Snoeck, Robert
通讯作者：
Snoeck, Robert
影响因子：
3.6
作者：
Aldern, KA;Ciesla, SL;Hostetler, KY
通讯作者：
Hostetler, KY
影响因子：
4.9
作者：
Choo, Hyunah;Beadle, James R.;Hostetler, Karl Y.
通讯作者：
Hostetler, Karl Y.
影响因子：
5.4
作者：
Adams, Mathew M.;Rice, Amanda D.;Moyer, R. W.
通讯作者：
Moyer, R. W.
影响因子：
7.3
作者：
Beadle, JR;Wan, WB;Hostetler, KY
通讯作者：
Hostetler, KY