کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1372593 | 981871 | 2011 | 6 صفحه PDF | دانلود رایگان |
We have previously reported the power of combining a 5′-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2′-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.
Various 6-substituted 2′-C-methylguanosines are prepared and converted to their 5′-ProTides. In almost every case the parent nucleosides are poorly active versus HCV while the ProTides are ca 100 fold more active.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 21, Issue 19, 1 October 2011, Pages 6007–6012