RESUMEN
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.
Asunto(s)
Diseño de Fármacos , Hepacivirus/enzimología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Estabilidad de Medicamentos , Hepacivirus/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Lactamas/síntesis química , Lactamas/farmacocinética , Lactamas/farmacología , Modelos Biológicos , Estructura Molecular , Inhibidores de Proteasas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Proteínas no Estructurales Virales/metabolismoRESUMEN
[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.
Asunto(s)
Hepacivirus/enzimología , Lactamas/síntesis química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Pirrolidinas/síntesis química , Serina Endopeptidasas/metabolismo , Proteínas no Estructurales Virales/antagonistas & inhibidores , Línea Celular , Diseño de Fármacos , Estabilidad de Medicamentos , Hepacivirus/efectos de los fármacos , Humanos , Lactamas/química , Estructura Molecular , Inhibidores de Proteasas/química , Pirrolidinas/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.