Discovery of 4′-azido-2′-deoxy-2′-C-methyl cytidine and prodrugs thereof: A potent inhibitor of Hepatitis C virus replication

• Published in: Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (9), p.3265-3268
• Main Authors: Nilsson, Magnus, Kalayanov, Genadiy, Winqvist, Anna, Pinho, Pedro, Sund, Christian, Zhou, Xiao-Xiong, Wähling, Horst, Belfrage, Anna-Karin, Pelcman, Michael, Agback, Tatiana, Benckestock, Kurt, Wikström, Kristina, Boothee, Mirva, Lindqvist, Anneli, Rydegård, Christina, Jonckers, Tim H.M., Vandyck, Koen, Raboisson, Pierre, Lin, Tse-I, Lachau-Durand, Sophie, de Kock, Herman, Smith, David B., Martin, Joseph A., Klumpp, Klaus, Simmen, Kenneth, Vrang, Lotta, Terelius, Ylva, Samuelsson, Bertil, Rosenquist, Åsa, Johansson, Nils Gunnar
• Format: Article
• Language: English
• Subjects: 4'-azidocytidine; analogs; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; antiviral activity; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antivirals; bioavailability; Biological and medical sciences; boceprevir; chemistry; cytidine; Cytidine - analogs & derivatives; Cytidine - pharmacology; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; design; Drug Discovery; General pharmacology; genotype 1 infection; Hepacivirus - drug effects; Hepatitis C virus; Medical sciences; Miscellaneous; NS5B polymerase; Nucleoside; Pharmacology. Drug treatments; Phosphoramidate; Prodrug; Prodrugs - pharmacology; Rats; resistance; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-directed RNA polymerase; telaprevir; Viral Nonstructural Proteins - antagonists & inhibitors; viral-hepatitis; virus replication; Virus Replication - drug effects
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2012.03.021

4′-Azido-2′-deoxy-2′-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC50 value of 1.2μM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4′-azido-2′-deoxy-2′-methylcytidine and prodrug derivatives thereof.