RESUMEN
We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.
Asunto(s)
Ácidos Borónicos/síntesis química , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Dominio Catalítico , Diseño de Fármacos , Hepacivirus/enzimología , Estructura Molecular , Serina/química , Relación Estructura-ActividadRESUMEN
Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Pirrolidinas/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacología , Sitios de Unión , Disponibilidad Biológica , Chlorocebus aethiops , Hepacivirus/enzimología , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacología , ARN Polimerasa Dependiente del ARN/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Células VeroRESUMEN
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.