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

  • J Med Chem. 2009 May 14;52(9):2971-8. doi: 10.1021/jm801595c.
David B Smith  1 ,  Genadiy Kalayanov ,  Christian Sund ,  Anna Winqvist ,  Tatiana Maltseva ,  Vincent J-P Leveque ,  Sonal Rajyaguru ,  Sophie Le Pogam ,  Isabel Najera ,  Kurt Benkestock ,  Xiao-Xiong Zhou ,  Ann C Kaiser ,  Hans Maag ,  Nick Cammack ,  Joseph A Martin ,  Steven Swallow ,  Nils Gunnar Johansson ,  Klaus Klumpp ,  Mark Smith
Affiliations
  • 1. Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, USA.
PMID: 19341305 DOI: 10.1021/jm801595c
Abstract

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 (EC(50) = 1.28 microM), 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 EC(50) 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).

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