RESUMO
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.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirimidinas/síntese química , RNA Viral/antagonistas & inibidores , Antivirais/farmacologia , Linhagem Celular Tumoral , Genótipo , Hepacivirus/fisiologia , Humanos , Pirimidinas/farmacologia , RNA Viral/biossíntese , Replicon/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Alcanos , Antivirais/farmacologia , Hepacivirus/enzimologia , Concentração Inibidora 50 , Replicon/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The SAR at C-5 of the 10-methoxy-2,2,4-trimethylbenzopyrano[3,4-f]quinoline core leading to identification of (-) anti 1-methylcyclohexen-3-yl as the optimum substituent that imparts minimal GR mediated in vitro transcriptional activation while maintaining full transcriptional repression is described. The in vitro profile of these candidates in human cell assays relevant to the therapeutic window of glucocorticoid modulators is outlined.
