RESUMO
HCV NS5B RNA-dependent RNA polymerase (NS5B) is essential for viral replication and is therefore considered a target for antiviral drug development. From our ongoing screening effort in the search for new anti-HCV agents, a novel inhibitor 1 with low microM activity against the HCV NS5B polymerase was identified. SAR analysis indicated the optimal substitution pattern required for activity, for example, carboxylic acid group at 2-position of thiophene ring. We describe the steps taken to identify and solve the bioactive conformation of derivative 6 through the use of the transferred NOE method (trNOE).
Assuntos
Antivirais/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Sulfonamidas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Piridinas/química , RNA Polimerase Dependente de RNA/química , Relação Estrutura-Atividade , Sulfonamidas/química , Tiofenos/química , Proteínas não Estruturais Virais/químicaRESUMO
Herein, we describe the structure-activity relationship (SAR) of N,N-disubstituted phenylalanine series of NS5B polymerase inhibitors of hepatitis C. The NS5B polymerase inhibitory activity of the most active compound exhibited an IC(50) of 2.7 microM.
Assuntos
Inibidores Enzimáticos/química , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and structure-activity relationships studies to improve potency are described.