RESUMO
[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
Assuntos
Hepacivirus/enzimologia , Lactamas/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirrolidinas/síntese química , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Linhagem Celular , Desenho de Fármacos , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Humanos , Lactamas/química , Estrutura Molecular , Inibidores de Proteases/química , Pirrolidinas/química , Proteínas não Estruturais Virais/metabolismoRESUMO
[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.