ABSTRACT
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.
Subject(s)
Drug Design , Guanosine/analogs & derivatives , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Pyrimidinones/administration & dosage , Pyrimidinones/chemical synthesis , Toll-Like Receptor 7/agonists , Administration, Oral , Antiviral Agents/pharmacology , Guanosine/pharmacology , Humans , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Pyrimidinones/chemistry , Pyrimidinones/pharmacokineticsABSTRACT
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.