EVALUATION OF WR250417 (A PROGUANIL ANALOG) FOR CAUSAL PROPHYLACTIC ACTIVITY IN THE PLASMODIUM-CYNOMOLGI MACACA-MULATTA MODEL

The Plasmodium cynomolgi-Macaca mulatta model has been used to test th e antimalarial activity of new drugs for both radical cure and causal prophylaxis. The proguanil analog WR250417 (also known as PS-15) was e valuated for causal prophylactic activity in rhesus monkeys infected w ith P. cynomolgi bastianelli. Four monkeys were orally dosed with 40 m g/kg/day of WR250417 over three days (-1, 0, and +1). Sporezoite-induc ed infection of P. cynomolgi was initiated on day 0 with 1 X 10(6) spo rozoites to each monkey. Compound WR250417 extended the prepatent peri od from an average of 8.5 days for controls (n = 2) to a mean of 18.3 days (range 18-19 days, n = 4) for drug-treated monkeys. Analysis of p lasma drug concentrations by high-performance liquid chromatography sh owed that the monkeys converted the WR250417 to its putative principal active metabolite WR99210 (a dihydrotriazine). These findings demonst rate that WR250417 and its principal metabolite do not prevent primary infection by P. cynomolgi.