期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 19, 页码 6007-6012出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.06.013
关键词
HCV; ProTide; Phosphoramidate; Nucleoside; Nucleotide; Polymerase; NS5B
资金
- Inhibitex, Inc.
We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate prodrug, 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. (C) 2011 Elsevier Ltd. All rights reserved.
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