Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 11; pp. 4400 - 4405
• Main Authors: Charman, Susan A., Arbe-Barnes, Sarah, Bathurst, Ian C., Brun, Reto, Campbell, Michael, Charman, William N., Chiu, Francis C. K., Chollet, Jacques, Craft, J. Carl, Creek, Darren J., Dong, Yuxiang, Matile, Hugues, Maurer, Melanie, Morizzi, Julia, Nguyen, Tien, Papastogiannidis, Petros, Scheurer, Christian, Shackleford, David M., Sriraghavan, Kamaraj, Stingelin, Lukas, Tang, Yuanqing, Urwyler, Heinrich, Wang, Xiaofang, White, Karen L., Wittlin, Sergio, Zhou, Lin, Vennerstrom, Jonathan L., Wellems, Thomas E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15-03-2011; National Acad Sciences
• Subjects: Adamantane - administration & dosage; Adamantane - analogs & derivatives; Adamantane - chemistry; Adamantane - pharmacokinetics; Adamantane - therapeutic use; Animals; Antimalarials; Antimalarials - administration & dosage; Antimalarials - chemistry; Antimalarials - pharmacokinetics; Antimalarials - therapeutic use; Artemisinins; Artemisinins - chemistry; Artemisinins - pharmacology; Artemisinins - therapeutic use; Biological Sciences; Blood; Blood plasma; Clinical trials; Dosage; Dose-Response Relationship, Drug; Drug Stability; Drugs; Erythrocytes; Half lives; Heterocyclic Compounds - administration & dosage; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacokinetics; Heterocyclic Compounds - therapeutic use; Iron - metabolism; Malaria; Malaria - drug therapy; Malaria - parasitology; Male; Mice; Ozonides; Parasites; Parasitic protozoa; Peroxides; Peroxides - administration & dosage; Peroxides - chemistry; Peroxides - pharmacokinetics; Peroxides - therapeutic use; Plasmodium berghei - physiology; Plasmodium falciparum; Rats; Rats, Sprague-Dawley; Time Factors; Treatment Outcome
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1015762108

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase lia trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC₄₀ values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghe/-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe (ll)-reactivity to elicit parasite death.