MK-4815, a potential new oral agent for treatment of malaria.
Malaria continues to have a significant impact on the health of the developing world. Efforts to combat this disease now focus on combination therapy in order to stem the emergence of resistant parasites. Continued efforts are needed to discover and develop new agents for use in combination antimalarial regimens. MK-4815 is a small molecule with antimalarial activity that was identified from a large pharmaceutical compound collection using a semiautomated version of a well-established in vitro assay for the erythrocytic stages of Plasmodium falciparum. In vitro studies indicate that the compound selectively accumulates in infected red blood cells and is most effective against the metabolically active late trophozoite/early schizont stages. A variety of drug-resistant field isolates of P. falciparum were found to be as sensitive to MK-4815 as the wild-type lines. MK-4815 is orally active in a P. berghei mouse model of acute malaria. In this model, where untreated animals succumb to infection 10 to 12 days postinfection, MK-4815 was completely curative when given as a single dose of 50 mg/kg, 2 doses of 25 mg/kg, or 4.5 doses of 12.5 mg/kg. In pharmacokinetic studies with mice and rhesus monkeys, MK-4815 demonstrated oral bioavailability and low clearance. In addition, MK-4815 is inexpensive to synthesize, an important characteristic for providing affordable antimalaria therapy to the developing world. The attractive biological and pharmaceutical profile of MK-4815 demonstrates its potential for use in combination with other agents in the fight against malaria.
Merck Research Laboratories, Department of Infectious Disease, Rahway, New Jersey, USA. maryann.powles@merck.com
Mary Ann
MA
Powles
John
J
Allocco
Lai
L
Yeung
Bakela
B
Nare
Paul
P
Liberator
Dennis
D
Schmatz
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D015996:Survival Rate; D053058:Trophozoites / Q000187:drug effects / Q000502:physiology
C574277:2-aminomethyl-3,5-di-tert-butylphenol; D000962:Antimalarials; D004338:Drug Combinations; D008744:Methylamines; D010636:Phenols