RESUMO
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
Assuntos
Disponibilidade Biológica , Desenho de Fármacos , Relação Estrutura-Atividade , Antivirais/farmacocinética , Química Farmacêutica , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C , Estrutura Molecular , RNA Polimerase Dependente de RNA , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.