RESUMEN
Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.
Asunto(s)
Antivirales/farmacocinética , Hepacivirus/efectos de los fármacos , Inhibidores de Proteasas/farmacocinética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Animales , Antivirales/síntesis química , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Diseño de Fármacos , Hepacivirus/enzimología , Enlace de Hidrógeno , Ratones , Pruebas de Sensibilidad Microbiana , Oligopéptidos/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Relación Estructura-Actividad , Replicación Viral/fisiologíaRESUMEN
Compounds of a combinatorial monocyclic beta-lactam library were found to be apparently uncompetitive inhibitors of HIV-1 protease, providing lead compounds for a new class of HIV protease inhibitors.
Asunto(s)
Diseño de Fármacos , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/química , beta-Lactamas/química , beta-Lactamas/farmacología , Animales , Unión Competitiva , Técnicas Químicas Combinatorias , Dimerización , Proteasa del VIH/metabolismo , Humanos , Virus de la Leucemia Murina/efectos de los fármacos , Virus de la Leucemia Murina/enzimología , Ratones , Modelos Moleculares , Estructura Molecular , Biblioteca de Péptidos , Relación Estructura-ActividadRESUMEN
We recently described the identification of an optimized alpha-ketoamide warhead for our series of HCV NS3.4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P(2). These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S(2) binding pocket as the defining pharmacophore for inhibition of the NS3.4A enzyme.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Oligopéptidos/farmacología , Prolina/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Hepatitis C/enzimología , Péptidos y Proteínas de Señalización Intracelular , Modelos Moleculares , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Prolina/síntesis química , Prolina/química , Relación Estructura-ActividadRESUMEN
The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed.
Asunto(s)
Hepacivirus/enzimología , Compuestos Macrocíclicos , Quinolinas , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Carbamatos/química , Carbamatos/metabolismo , Hepacivirus/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/metabolismo , Proteínas no Estructurales Virales/metabolismoRESUMEN
Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead. The SAR of the P1 and P2 inhibitor positions is discussed.