title: Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase.
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.
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Jonckers
authors.forename: Koen
authors.initials: K
authors.lastname: Vandyck
authors.forename: Leen
authors.initials: L
authors.lastname: Vandekerckhove
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Abdellah
authors.initials: A
authors.lastname: Tahri
authors.forename: Steven
authors.initials: S
authors.lastname: Van Hoof
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.forename: Jan Martin
authors.initials: JM
authors.lastname: Berke
authors.forename: Sophie
authors.initials: S
authors.lastname: Lachau-Durand
authors.forename: Bart
authors.initials: B
authors.lastname: Stoops
authors.forename: Laurent
authors.initials: L
authors.lastname: Leclercq
authors.forename: Gregory
authors.initials: G
authors.lastname: Fanning
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Magnus
authors.initials: M
authors.lastname: Nilsson
authors.forename: Åsa
authors.initials: Å
authors.lastname: Rosenquist
authors.forename: Kenny
authors.initials: K
authors.lastname: Simmen
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012263:Ribonucleosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011355:Prodrugs; D012263:Ribonucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase