1. Academic Validation
  2. Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase

Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase

  • J Med Chem. 2014 Mar 13;57(5):1836-44. doi: 10.1021/jm4015422.
Tim H M Jonckers 1 Koen Vandyck Leen Vandekerckhove Lili Hu Abdellah Tahri Steven Van Hoof Tse-I Lin Leen Vijgen Jan Martin Berke Sophie Lachau-Durand Bart Stoops Laurent Leclercq Gregory Fanning Bertil Samuelsson Magnus Nilsson Åsa Rosenquist Kenny Simmen Pierre Raboisson
Affiliations

Affiliation

  • 1 Janssen Infectious Diseases - Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
Abstract

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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