Dual pro-drugs of 2′-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus

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.

Graphical abstractVarious 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 full-size imageDownload as PowerPoint slide