2'-Deoxy-2'-spirocyclopropylcytidine revisited: a new and selective inhibitor of the hepatitis C virus NS5B polymerase

J Med Chem. 2010 Nov 25;53(22):8150-60. doi: 10.1021/jm101050a.

Tim H M Jonckers ¹, Tse-I Lin, Christophe Buyck, Sophie Lachau-Durand, Koen Vandyck, Steven Van Hoof, Leen A M Vandekerckhove, Lili Hu, Jan Martin Berke, Leen Vijgen, Lieve L A Dillen, Maxwell D Cummings, Herman de Kock, Magnus Nilsson, Christian Sund, Christina Rydegård, Bertil Samuelsson, Asa Rosenquist, Gregory Fanning, Kristof Van Emelen, Kenneth Simmen, Pierre Raboisson

Affiliations

Affiliation

1 Tibotec BVBA, A Division of Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium. tjoncker@its.jnj.com

PMID: 21033671 DOI: 10.1021/jm101050a

Abstract

The current therapy for hepatitis C virus (HCV) Infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) of 7.3 μM measured in the Huh7-Rep cell line and no associated cytotoxicity (CC(50) > 98.4 μM). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated. The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.

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