title: Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria.
abstract: 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 IIa 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 IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-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(II)-reactivity to elicit parasite death.
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Sarah
authors.initials: S
authors.lastname: Arbe-Barnes
authors.forename: Ian C
authors.initials: IC
authors.lastname: Bathurst
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.forename: Jacques
authors.initials: J
authors.lastname: Chollet
authors.forename: J Carl
authors.initials: JC
authors.lastname: Craft
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Hugues
authors.initials: H
authors.lastname: Matile
authors.forename: Melanie
authors.initials: M
authors.lastname: Maurer
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Tien
authors.initials: T
authors.lastname: Nguyen
authors.forename: Petros
authors.initials: P
authors.lastname: Papastogiannidis
authors.forename: Christian
authors.initials: C
authors.lastname: Scheurer
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Kamaraj
authors.initials: K
authors.lastname: Sriraghavan
authors.forename: Lukas
authors.initials: L
authors.lastname: Stingelin
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Tang
authors.forename: Heinrich
authors.initials: H
authors.lastname: Urwyler
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006571:Heterocyclic Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007501:Iron / Q000378:metabolism; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D010545:Peroxides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010962:Plasmodium berghei / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D037621:Artemisinins; D006571:Heterocyclic Compounds; D010545:Peroxides; C031327:artemisinin; D007501:Iron; D000218:Adamantane; C558165:artefenomel