ABSTRACT
4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 µM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.
Subject(s)
Antiviral Agents/chemistry , Cytidine/analogs & derivatives , Deoxycytidine/analogs & derivatives , Hepacivirus/drug effects , Prodrugs/pharmacology , Animals , Antiviral Agents/pharmacology , Cytidine/pharmacology , Deoxycytidine/pharmacology , Drug Discovery , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Rats , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effectsABSTRACT
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.