RESUMO
A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Peptídeos Cíclicos/química , Ácidos Fosfínicos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cães , Inibidores Enzimáticos/síntese química , Hepacivirus/enzimologia , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/farmacologia , SuínosRESUMO
A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.