RESUMEN
Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase.
Asunto(s)
Inhibidores de Proteasas/química , Uracilo/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sustitución de Aminoácidos , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Cinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Sitio de Iniciación de la Transcripción , Uracilo/síntesis química , Uracilo/química , Uracilo/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
The synthesis of several pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine analogs is described with one such analog possessing subnanomolar potency in both genotype 1a and 1b cell culture HCV replicon assays.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Pirimidinas/síntesis química , ARN Viral/antagonistas & inhibidores , Antivirales/farmacología , Línea Celular Tumoral , Genotipo , Hepacivirus/fisiología , Humanos , Pirimidinas/farmacología , ARN Viral/biosíntesis , Replicón/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.
Asunto(s)
Virus de la Influenza A/enzimología , Virus de la Influenza B/enzimología , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/química , Pirrolidinas/síntesis química , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Substituted 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed. It was found that the saturated alkane dialkyl units provided the most active analogs.
Asunto(s)
Antivirales/síntesis química , Benzotiadiazinas/síntesis química , Benzotiadiazinas/farmacología , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Alcanos , Antivirales/farmacología , Hepacivirus/enzimología , Concentración 50 Inhibidora , Replicón/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed.
Asunto(s)
Benzotiadiazinas , Inhibidores Enzimáticos , Sulfonamidas , Proteínas no Estructurales Virales/antagonistas & inhibidores , Benzotiadiazinas/síntesis química , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/químicaRESUMEN
Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.