ANTIPICORNAVIRUS ACTIVITY OF SCH-47802 AND ANALOGS - IN-VITRO AND IN-VIVO STUDIES

SCH 47802 and its derivatives are potent inhibitors of enteroviruses i n vitro. The IC50 for SCH 47802 ranges from 0.03 to 10 mu g/ml when te sted against a spectrum of enteroviruses in plaque reduction assays. T he compounds have in vitro therapeutic indices of at least 81 based on viral cytopathic effect (CPE) assays. The in vitro activity of SCH 47 802 translates into in vivo activity in the murine model of poliovirus encephalitis. In an oral dosing regimen, SCH 47802 protects mice from mortality at 60 mg/kg per day. Consistent with the in vivo efficacy, pharmacokinetic analyses after oral dosing with SCH 47802 demonstrate serum levels of the compound above the in vitro IC50 for poliovirus fo r at least 4 h. SCH 47802 and its active analogs stabilize poliovirus to thermal inactivation indicating that the compounds bind to the viru s capsid. Mechanistic studies with poliovirus indicate that SCH 47802 acts early in viral infection. This series of molecules represents pot ential candidates for the treatment of human enterovirus infections.