Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
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DOI：
10.1021/jm060776w
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发表时间：
2006-11-30
影响因子：
7.3
通讯作者：
Balzarini, Jan
中科院分区：
文献类型：
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作者：
McGuigan, Christopher;Hassan-Abdallah, Alshaimaa;Balzarini, Jan
报道了氨基磷酸酯前核苷酸（ProTide）技术在抗病毒药物碳环L-d4 A（L-Cd 4A）中的应用。L-Cd 4A的苯甲基丙氨酰基母体磷酰胺酯前药通过格氏介导的氯代磷酸酯反应制备，并产生具有显著提高的抗HIV（2600倍）和HBV活性的化合物。我们描述了磷酰胺酯前药的芳基、酯和氨基酸区域的修饰，以及这些变化如何影响抗病毒活性和代谢稳定性。观察到HIV和HBV的单独和不同SAR。此外，由D-核苷D-Cd 4A和双脱氧类似物L-CddA和D-CddA制备磷酰胺酯前药。这些化合物显示出比母体药物更适度的效力改善。总之，磷酰胺酯前药方法在应用于L-Cd 4A时非常成功，体外抗HIV的效力提高高达9000倍。为了进行临床前候选药物选择，我们使用食蟹猴肝脏和肠道S9组分进行了代谢稳定性研究。
We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.