Nucleotide Prodrugs of 2鈥?Deoxy-2鈥?spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase

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• 作者：Tim H. M. Jonckers ; Koen Vandyck ; Leen Vandekerckhove ; Lili Hu ; Abdellah Tahri ; Steven Van Hoof ; Tse-I Lin ; Leen Vijgen ; Jan Martin Berke ; Sophie Lachau-Durand ; Bart Stoops ; Laurent Leclercq ; Gregory Fanning ; Bertil Samuelsson ; Magnus Nilsson ; 脜sa Rosenquist ; Kenny Simmen ; Pierre Raboisson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1836-1844
• 全文大小：356K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2鈥?deoxy-2鈥?spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC₅₀ values ranging from 0.2 to >98 渭M, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC₅₀ > 98.4 渭M). Confirming recent findings, the 2鈥?spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.