PS-15 - A POTENT, ORALLY-ACTIVE ANTIMALARIAL FROM A NEW CLASS OF FOLIC-ACID ANTAGONISTS

A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS- 1 5 yloxy)-N'-(1-methylethyl)-imidocarbonimidicdiamide hydrochlori de), has significant activity against drug-resistant Plasmodium falcip arum. It is not cross-resistant with other inhibitors of DHFR (e.g., p yrimethamine and cycloguanil). Although it bears similarities to progu anil, PS-15 represents a new antifolate class of drugs that we have na med oxyguanils or hydroxylamine-derived biguanides. This compound disp lays intrinsic antimalarial activity and also is metabolized in vivo t o WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was mo re active than proguanil, and the putative metabolite, WR99210, was mo re active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered ora lly to mice infected with P. berghei. When administered orally to Aotu s monkeys infected with multidrug-resistant P. falciparum, PS-15 was m ore active than either proguanil or WR99210. In 1973, WR99210 underwen t clinical trials for safety and tolerance in volunteers. The trials s howed gastrointestinal intolerance and limited bioavailability; furthe r development of the drug was abandoned. Because PS-15 has intrinsic a ntimalarial activity, is not cross-resistant with other DHFR inhibitor s, and can be metabolized to WR99210 in vivo, oral administration of t his new drug should circumvent the shortcomings and retain the advanta ges found with both proguanil and WR99210.