RESUMO
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.
Assuntos
Antivirais/química , Citidina/análogos & derivados , Desoxicitidina/análogos & derivados , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Antivirais/farmacologia , Citidina/farmacologia , Desoxicitidina/farmacologia , Descoberta de Drogas , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Ratos , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacosRESUMO
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.