Antimalarial activities of various 4-pyridinemethanols with special attention to WR-172,435 and WR-180,409.
Pilot appraisals of the activities of 10 specially selected 2,6-substituted-4-pyridinemethanols against acute Plasmodium falciparum infections in owl monkeys identified three derivatives that were two to three times as active as chloroquine against infections with a 4-aminoquinoline-susceptible strain and, at the same doses, were equally effective against infections with a strain fully resistant to treatment with maximally tolerated doses of chloroquine, quinine, and pyrimethamine. Two of these derivatives, WR-172,435 and WR-180,409, deemed worthy of evaluation in human volunteers, were studied in greater depth in owl monkeys infected with either the multidrug-resistant Smith strain of P. falciparum or the pyrimethamine-resistant Palo Alto strain of P. vivax. These studies showed (i) that at the same total oral dose, 3-day and 7-day treatment schedules were equally effective and slightly superior to a single-dose schedule; (ii) that WR-172,435 was slightly more active than WR-180,409 in each treatment regimen; (iii) that intravenous delivery of WR-180,409 phosphate was feasible and effective; (iv) that both compounds effected control of parasitemia more rapidly than any standard or newly discovered antimalarial drug; and (v) that WR-172,435 and WR-180,409 had therapeutic indexes at least four to eight times those exhibited by chloroquine in infections with 4-aminoquinoline-susceptible strains, indexes retained by these pyridinemethanols against infections with various drug-resistant strains.
D000818:Animals; D001029:Aotus trivirgatus; D005260:Female; D000882:Haplorhini; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D000432:Methanol / Q000031:analogs & derivatives / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use*; D010962:Plasmodium berghei; D010963:Plasmodium falciparum; D010966:Plasmodium vivax; D011725:Pyridines / Q000627:therapeutic use*
D010880:Piperidines; D011725:Pyridines; C017813:WR 172435; D000432:Methanol