In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug.
WIN 54954 (5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl]-3- methylisoxazole) is a new member of the class of broad-spectrum antipicornavirus compounds known to bind in a hydrophobic pocket within virion capsid protein VP1. In plaque reduction assays, WIN 54954 reduced plaque formation of 50 of 52 rhinovirus serotypes (MICs ranged from 0.007 to 2.2 micrograms/ml). A concentration of 0.28 microgram/ml was effective in inhibiting 80% of the 52 serotypes tested (EC80). WIN 54954 was also effective in inhibiting 15 commonly isolated enteroviruses, with an EC80 of 0.06 microgram/ml. Furthermore, WIN 54954 was effective in reducing the yield of two selected enteroviruses in cell culture by 90% at concentrations approximately equal to their MICs. The therapeutic efficacy of intragastrically administered WIN 54954 was assessed in suckling mice infected with coxsackievirus A-9 or echovirus type 9 (Barty) 2.5 days prior to initiation of therapy. Single daily doses of 2 and 100 mg/kg protected 50% of the mice from developing paralysis (PD50) following infection with coxsackievirus A-9 and echovirus-9, respectively. At the PD50 doses for these two viruses, levels of WIN 54954 in serum were maintained above the in vitro MICs for a significant portion of the dosing interval. The dose-dependent reduction in viral titers observed in coxsackievirus A-9-infected mice correlated well with the therapeutic dose response. The potency and spectrum of WIN 54954 make it a potentially useful compound for the treatment of human enterovirus and rhinovirus infections.
Woods
M G
MG
Department of Virology and Oncopharmacology, Sterling Research Group, Rensselaer, New York 12144.
Diana
G D
GD
Rogge
M C
MC
Otto
M J
MJ
Dutko
F J
FJ
McKinlay
M A
MA
D000818:Animals; D000833:Animals, Suckling; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003384:Coxsackievirus Infections / Q000188:drug therapy; D003470:Culture Media; D004457:Echovirus Infections / Q000188:drug therapy; D005260:Female; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008813:Mice, Inbred ICR; D010080:Oxazoles / Q000494:pharmacology*; D010849:Picornaviridae / Q000187:drug effects* / Q000502:physiology; D012229:Rhinovirus / Q000187:drug effects; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D003470:Culture Media; D007555:Isoxazoles; D010080:Oxazoles; C062554:Win 54954