Design, Synthesis and Antiviral Evaluation of 2′-C-Methyl Branched Guanosine Pronucleotides: The Discovery of IDX184, a Potent Liver-Targeted HCV Polymerase Inhibitor

Abstract

Background: Ribonucleoside analogs possessing a β-methyl substituent at the 2′-position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure–activity relationships of several phosphoramidate diester derivatives of 2′-C-methylguanosine (2′-MeG). Conclusion: The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.

KEYWORDS:

• 2′-C-methyl-branched guanosine derivatives
• HCV polymerase inhibitors
• pronucleotides

Acknowledgements

We gratefully acknowledge Fanti Maura (former Idenix Research Associate I – Biology) and A Cadeddu (former Idenix Research Associate II – Biology) for excellent technical assistance, and T Convard (Idenix SARL Senior Manager, Molecular Modelling & Chemoinformatics) for logP calculation support. We also thank C Périgaud (Professor, UMR 5247 CNRS-Université Montpellier-ENSCM) and S Peyrottes (CNRS Research Director, UMR 5247 CNRS- Université Montpellier-ENSCM) for helpful discussions. We are indebted to C Dousson (Idenix SARL Senior Director Medicinal Chemistry – Site Head) for critical reading of the manuscript.

Dedication

This paper is dedicated to Jean-Louis Imbach on the occasion of his 79th birthday in recognition of his pioneering and outstanding contributions in the field of pronucleotide approaches.

Financial & competing interests disclosure

G Sizun is particularly grateful to the former Idenix Pharmaceuticals Company and to the French National Association for Technical Research (Association Nationale de la Recherche Technique [ANRT]) for a doctoral fellowship (Grant No. 901/2004). The authors have no other relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

G Sizun is particularly grateful to the former Idenix Pharmaceuticals Company and to the French National Association for Technical Research (Association Nationale de la Recherche Technique [ANRT]) for a doctoral fellowship (Grant No. 901/2004). The authors have no other relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript apart from those disclosed.