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Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase. 2014
Tim H M Jonckers, and
Koen Vandyck, and
Leen Vandekerckhove, and
Lili Hu, and
Abdellah Tahri, and
Steven Van Hoof, and
Tse-I Lin, and
Leen Vijgen, and
Jan Martin Berke, and
Sophie Lachau-Durand, and
Bart Stoops, and
Laurent Leclercq, and
Gregory Fanning, and
Bertil Samuelsson, and
Magnus Nilsson, and
Åsa Rosenquist, and
Kenny Simmen, and
Pierre Raboisson
Janssen Infectious Diseases - Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
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'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2'-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.
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