RESUMEN
Isoquinoline-based non-nucleoside inhibitors of HCV NS5b RNA-dependent RNA-polymerase are described. The synthesis and structure-activity relationships are detailed, along with enzyme and cellular activity.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Isoquinolinas/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Isoquinolinas/química , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.
Asunto(s)
Antivirales/síntesis química , Benzotiadiazinas/síntesis química , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hepacivirus/efectos de los fármacos , Tiazinas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Antivirales/farmacología , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Biología Computacional , Simulación por Computador , Cristalografía por Rayos X , ARN Polimerasas Dirigidas por ADN/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Unión Proteica , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacología , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Tiazoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Haplorrinos , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinética , Proteínas no Estructurales Virales/metabolismoRESUMEN
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
Asunto(s)
Antivirales/química , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Hepacivirus/efectos de los fármacos , Quinolinas/química , Quinolonas/química , Tiazinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Simulación por Computador , Cristalografía por Rayos X , ARN Polimerasas Dirigidas por ADN/metabolismo , Perros , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolonas/síntesis química , Quinolonas/farmacología , Ratas , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/farmacología , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Pirrolidinonas/química , Tiazinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
Detailed experimental approaches toward the pentacyclic Stemona alkaloids tuberostemonine and didehydrotuberostemonine and the close analogue 13-epituberostemonine are described. The syntheses originate with a hydroindolinone derivative that can be obtained on a large scale in a single step from carbobenzoxy-protected l-tyrosine. Highlights of the conversion of this hydroindolinone to the target structures are the three-fold use of ruthenium catalysts, first in azepine ring-closing metathesis and then in alkene isomerization and cross-metathesis propenyl-vinyl exchange, as well as the stereoselective attachment of a gamma-butyrolactone ring to a tetracycle core structure by use of a lithiated asymmetric bicyclo[3.2.1]octane (ABO) ortho ester. Structural analysis by density functional theory (DFT) methods revealed that the ease of oxidation of the natural product is likely due to the conformational preferences of the pyrrolidine and the fused cyclohexane rings.