The Design, Synthesis, and Antiviral Activity of Monofluoro and Difluoro Analogues of 4′-Azidocytidine against Hepatitis C Virus Replication: The Discovery of 4′-Azido-2′-deoxy-2′-fluorocytidine and 4′-Azido-2′-dideoxy-2′,2′-difluorocytidine

被引：80

作者：

Smith, David B. ^{[1
]}

Kalayanov, Genadiy ^{[2
]}

Sund, Christian ^{[2
]}

Winqvist, Anna ^{[2
]}

Maltseva, Tatiana ^{[2
]}

Leveque, Vincent J. -P. ^{[1
]}

Rajyaguru, Sonal ^{[1
]}

Le Pogam, Sophie ^{[1
]}

Najera, Isabel ^{[1
]}

Benkestock, Kurt ^{[2
]}

Zhou, Xiao-Xiong ^{[2
]}

Kaiser, Ann C. ^{[1
]}

Maag, Hans ^{[1
]}

Cammack, Nick ^{[1
]}

Martin, Joseph A. ^{[1
]}

Swallow, Steven ^{[1
]}

Johansson, Nils Gunnar ^{[2
]}

Klumpp, Klaus ^{[1
]}

Smith, Mark ^{[1
]}

机构：

[1] Roche Palo Alto LLC, Palo Alto, CA 94304 USA

[2] Medivir AB, Dept Med Chem, SE-14144 Huddinge, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 09期

关键词：

POTENT INHIBITOR; GEMCITABINE; R1479;

D O I：

10.1021/jm801595c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of 4'-azidocytidine (3) (R1479) (J. Biol. Chem. 2006, 281, 3793; Bioorg. Med. Chem. Lett. 2007, 17, 2570) as a potent inhibitor of RNA synthesis by NS5B (EC50 = 1.28 mu M), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of several monofluoro and difluoro derivatives of 4'-azidocytidine. The most potent compounds in this series were 4'-azido-2'-deoxy-2',2'-difluorocytidine and 4'-azido-2'-deoxy-2'-fluoroarabinocytidine with antiviral EC50 of 66 nM and 24 nM in the HCV replicon system, respectively. The structure-activity relationships within this series were discussed. which led to the discovery of these novel nucleoside analogues with the most potent compound, showing more than a 50-fold increase in antiviral potency as compared to 4'-azidocytidine (3).

引用

页码：2971 / 2978

页数：8

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