1. β-d-2′-α-F-2′-β-C-Methyl-6-O-substituted 3′,5′-cyclic phosphate nucleotide prodrugs as inhibitors of hepatitis C virus replication: A structure–activity relationship study
- Author
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Du, Jinfa, Bao, Donghui, Chun, Byoung-Kwon, Jiang, Ying, Ganapati Reddy, P., Zhang, Hai-Ren, Ross, Bruce S., Bansal, Shalini, Bao, Haiying, Espiritu, Christine, Lam, Angela M., Murakami, Eisuke, Niu, Congrong, Micolochick Steuer, Holly M., Furman, Phillip A., Otto, Michael J., and Sofia, Michael J.
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PRODRUGS , *HEPATITIS C virus , *VIRAL replication , *NUCLEOSIDES , *LIVER cells , *LABORATORY rats - Abstract
Abstract: The 3′,5′-cyclic phosphate prodrug 9-[β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribofuranosyl]-2-amino-6-ethoxypurine, PSI-352938 1, has demonstrated promising anti-HCV efficacy in vitro and in human clinical trials. A structure–activity relationship study of the nucleoside 3′,5′-cyclic phosphate series of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylribofuranosyl nucleoside prodrugs was undertaken and the anti-HCV activity and in vitro safety profile were assessed. Cycloalkyl 3′,5′-cyclic phosphate prodrugs were shown to be significantly more potent as inhibitors of HCV replication than branched and straight chain alkyl 3′,5′-cyclic phosphate prodrugs. No cytotoxicity and mitochondrial toxicity for prodrugs 12, 13 and 19 were observed at concentrations up to 100μm in vitro. Cycloalkyl esters of 3′,5′-cyclic phosphate nucleotide prodrugs demonstrated the ability to produce high levels of active triphosphate in clone-A cells and primary human hepatocytes. Compounds 12, 13 and 19 also demonstrated the ability to effectively deliver in vivo high levels of active nucleoside phosphates to rat liver. [Copyright &y& Elsevier]
- Published
- 2012
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