Abstract
Nineteen phenoxypyridinecarbonitriles were initially evaluated for their in vitro activity against rhinoviruses (RV) 1A, 2, and 64 and coxsackievirus (Cox) A21 and for their oral prophylactic and therapeutic activity in Swiss albino mice challenged with Cox A21. On the basis of the results of these studies, one compound, 6-(3,4-dichlorophenoxy)-3-(ethylthio)-2-pyridinecarbonitrile, was selected for further evaluation. Expanded in vitro spectrum of activity studies showed that the MIC causing a 50% reduction in viral cytopathic effect in infected cultures (MIC50) was 3.0 micrograms/ml or less against 11 of 20 RV serotypes tested. The compound was only moderately active (MIC50, 5 to 7 micrograms/ml) against four of the RV serotypes evaluated, while RV 4, 5, 8, 13 and Hank's were relatively resistant to compound inhibition. Of the nine enteroviruses studied, only Cox A21, echovirus 12, poliovirus 2, and enterovirus 70 were inhibited at compound concentrations of less than 2.0 micrograms/ml. The compound provided significant protection to mice infected with a normally lethal dose of Cox A21 when administered in a single oral dose of 150 mg/kg (P less than 0.01) and during a regimen of continuous oral doses of 37.5 mg/kg per day (P less than 0.001). Mechanism of action studies indicated that the compound inhibited picornavirus uncoating or some earlier virus-host cell-associated event.
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