RESUMO
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.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirrolidinas/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Chlorocebus aethiops , Hepacivirus/enzimologia , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacologia , RNA Polimerase Dependente de RNA/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Células VeroRESUMO
Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.