RESUMO
SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.
Assuntos
Inibidores de Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , HIV-1/enzimologia , Microssomos Hepáticos/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacologia , Animais , Cães , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacocinética , Haplorrinos , Humanos , Naftiridinas/química , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polymerase. The best compound has an IC(50) of 200 nM and EC(50) of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of 1 with HCV NS5B was obtained at a resolution of 2.2A, revealing that the inhibitor is covalently linked with Cys 366 of the 'primer-grip'. Furthermore, it makes considerable contacts with the C-terminus, beta-loop, and more importantly, to the active-site of the enzyme. The uniqueness of this binding mode offers a new insight for the rational design of novel inhibitors for HCV NS5B polymerase.
