RESUMEN
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.
Asunto(s)
Antivirales/farmacología , Química Farmacéutica/métodos , Hepacivirus/enzimología , Quinolonas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitio Alostérico , Antivirales/síntesis química , Sitios de Unión , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Enlace de Hidrógeno , Hidrólisis , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Quinolonas/síntesis química , Relación Estructura-Actividad , Proteínas no Estructurales Virales/química , Rayos XRESUMEN
Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.
Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Quinolonas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Antivirales/síntesis química , Antivirales/farmacología , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
Efforts towards developing orally bioavailable HIV-1 maturation inhibitors starting from betulinic acid 1 are described. SAR resulted in improved potency, physicochemical properties, and enhanced oral absorption in rats.