oz-439 and artemisinin

Combination medicines including an artemisinin are the mainstay of antimalarial therapy. Artemisinins are potent embryotoxicants in animal species due to their trioxane moiety.. As part of its development, the new synthetic trioxolane antimalarial artefenomel (OZ439) was tested in rat whole embryo culture and in rat embryo-fetal toxicity studies with dosing throughout organogenesis or with a single dose on Gestational Day (GD) 12. The single-dose studies included groups treated with artesunate to allow a direct comparison of the embryotoxicity of the two antimalarials and included toxicokinetics hematology and histological examination of embryos. In addition, the distribution of artefenomel-related material in plasma was determined after the administration of. Artefenomel and artesunate showed similar patterns of embryotoxicity including cardiovascular defects and resorption with a steep dose-response. They both also caused a depletion of circulating embryonic erythroblasts both in vitro and in vivo and decreases in maternal reticulocyte count. However, artefenomel was ∼250-fold less potent than the active metabolite of artesunate (dihydroartemisinin) as an embryotoxicant in vitro. The safety margin (based on AUC) for artefenomel administered on GD 12 was approximately 100-fold greater than that for artesunate. Also, unlike artesunate, artefenomel was not a selective developmental toxicant.. The lesser embryotoxicity of artefenomel is likely linked to its original design which included two blocking side groups that had been introduced to lower the reactivity with ferrous iron. Our data support the hypothesis that artefenomel's improved safety margin is linked to a lower potential for inhibiting heme biosynthesis in embryonic erythroblasts.

Topics: Adamantane; Animals; Antimalarials; Artemisinins; Artesunate; Benzoxazines; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Fetal Development; Gestational Age; Heme; Organ Culture Techniques; Organogenesis; Peroxides; Phthalimides; Rats

Recently published data suggest that artemisinin derivatives and synthetic peroxides, such as the ozonides OZ277 and OZ439, have a similar mode of action. Here the cross-resistance of OZ277 and OZ439 and four additional next-generation ozonides was probed against the artemisinin-resistant clinical isolate Plasmodium falciparum Cam3.I, which carries the K13-propeller mutation R539T (Cam3.I. The previously described in vitro ring-stage survival assay (RSA. At the pharmacologically relevant concentration of 700 nM, all six ozonides were highly effective against the dihydroartemisinin-resistant P. falciparum Cam3.I. The absence of in vitro cross-resistance against the artemisinin-resistant clinical isolate Cam3.I

Topics: Adamantane; Antimalarials; Artemisinins; Drug Resistance; Heterocyclic Compounds, 1-Ring; Peroxides; Plasmodium falciparum; Spiro Compounds

The ring-stage susceptibility assay was modified to quantify the susceptibilities of multiple strains of control and delayed-clearance phenotype (DCP) Plasmodium falciparum strains to seven endoperoxide antimalarial drugs. The susceptibility of all of the DCP lines to six of the drugs was lower than that of the controls. In contrast, DCP parasites did not show reduced susceptibility to the synthetic endoperoxide drug OZ439. These data show that it is possible to circumvent emerging artemisinin resistance with a modified endoperoxide drug.

Topics: Adamantane; Antimalarials; Artemether; Artemisinins; Dose-Response Relationship, Drug; Drug Resistance; Heterocyclic Compounds, 1-Ring; Inactivation, Metabolic; Lethal Dose 50; Microbial Sensitivity Tests; Peroxides; Plasmodium falciparum; Spiro Compounds

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.

Topics: Adamantane; Animals; Antimalarials; Artemisinins; Dose-Response Relationship, Drug; Drug Stability; Heterocyclic Compounds; Iron; Malaria; Male; Mice; Peroxides; Plasmodium berghei; Rats; Rats, Sprague-Dawley; Time Factors; Treatment Outcome