RESUMO
ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.
Assuntos
Desenho de Fármacos , Guanosina/análogos & derivados , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pirimidinonas/administração & dosagem , Pirimidinonas/síntese química , Receptor 7 Toll-Like/agonistas , Administração Oral , Antivirais/farmacologia , Guanosina/farmacologia , Humanos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pirimidinonas/química , Pirimidinonas/farmacocinéticaRESUMO
Based upon observations from our initial findings, additional myxopyronin B analogs have been prepared and tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against Escherichia coli and Staphylococcus aureus.