Synthesis and anti-HCV activity of 3′,4′-oxetane nucleosides

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• 作者：Wonsuk Chang ; Jinfa Du ; Suguna Rachakonda ; Bruce S. Ross ; Serge Convers-Reignier ; Wei T. Yau ; Jean-Francois Pons ; Eisuke Murakami ; Haiying Bao ; Holly Micolochick Steuer ; Phillip A. Furman ; Michael J.
• 关键词：Antivirals ; Hepatitis C ; HCV ; RG7128 ; NS5B polymerase ; Bicyclic nucleosides
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 August 2010
• 年：2010
• 卷：20
• 期：15
• 页码：4539-4543
• 全文大小：443 K

文摘

Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3′,4′-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2′-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates.