RESUMEN
A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos/química , Nucleósidos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Antivirales/farmacocinética , Células CACO-2 , Línea Celular , Cricetinae , Descubrimiento de Drogas , Farmacorresistencia Viral , Halogenación , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C/tratamiento farmacológico , Humanos , Metilación , Simulación del Acoplamiento Molecular , Nucleósidos/farmacocinética , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacocinética , Ácidos Fosfóricos/farmacología , Mutación Puntual , Profármacos/química , Profármacos/farmacocinética , Profármacos/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
The first synthesis of 1'-C-CN, 2'-F, 2'-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1'-C-CN, 2'-C-Me as well as the 2'-F, 2'-C-Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Amidas/química , Amidas/farmacología , Línea Celular , Halogenación , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Metilación , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacología , Profármacos/química , Profármacos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Replicón/efectos de los fármacosRESUMEN
The first synthesis of 1'-cyano-2'-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1'-unsubstituted counterparts and to the related 1'-cyano-2'-C-methyl C-nucleoside parent of GS-6620.
