Characterization of the two major CYP450 metabolites of ozonide (1,2,4-trioxolane) OZ277

Zhou, Lin; Alker, André; Ruf, A.; Wang, Xiaofang; Chiu, Francis Chi Keung; Morizzi, Julia; Charman, Susan A.; Charman, William N.; Scheurer, Christian; Wittlin, Sergio; Dong, Yuxiang; Hunziker, Daniel; Vennerstrom, Jonathan L.

doi:10.1016/j.bmcl.2008.01.087

Cited by 36 publications

(41 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The focus of initial investigations was to define the mechanistic basis for clearance of the first generation ozonide, OZ277, and identify synthetic strategies to reduce clearance, and subsequently increase the half-life and overall exposure profile. Previous studies indicated a role of cytochrome P450 (CYP450)-mediated metabolism in the clearance of OZ277, resulting in the formation of inactive adamantane-hydroxylated metabolites (19). In vivo studies with OZ277 in rats (Fig.…”

Section: Resultsmentioning

confidence: 97%

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

Charman

Arbe-Barnes²,

Bathurst

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

335

365

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 97%

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

Charman

Arbe-Barnes²,

Bathurst

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

335

365

View full text Add to dashboard Cite

show abstract

“…DHA was obtained from Chongqing Holley Wuling Mountain Pharmaceutical Co. Ltd, and artesunate from Guilin Pharmaceutical Co. Ltd.; artemisone, DSM265 [60], OZ277 [70], MMV390048 [71], OZ439 [72], OZ381 [73], P218 [59] and carbaOZ277 [74] were synthesized as previously described. Erlotinib and imatinib were supplied by LC-Laboratories (Woburn, MA, USA), cisplatin and vincristine by Sigma-Aldrich (Deisenhofen, Germany) and dasatinib by SanxinChemPharma (Shijiazhuang, China).…”

Section: Methodsmentioning

confidence: 99%

Anticancer Properties of Distinct Antimalarial Drug Classes

et al. 2013

Self Cite

View full text Add to dashboard Cite

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

show abstract

“…Thus, the prolonged circulation of OZ418 is most likely due to its reduced clearance rate and possibly an increased volume of distribution. Previous studies of OZ277 have shown that although CYP450 metabolism contributed significantly to OZ277 elimination (30,70), the major clearance mechanism most probably proceeded via peroxide bond reduction by endogenous Fe(II) sources in blood and tissues (30,31). Our data on OZ78 and OZ418 reactivity toward Fe(II) at 37°C (see Fig.…”

Section: Corresponding To [M ϫ Ch 2 C(o)oh]mentioning

confidence: 47%

Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry

Leonidova

Vargas

Huwyler

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

One of the major neglected tropical diseases, schistosomiasis, is currently treated and controlled with a single drug, praziquantel. The quest for an alternative drug is fueled by the lack of activity of praziquantel against juvenile Schistosoma worms and the fear of emerging resistance. The synthetic ozonide OZ418 has shown high activity against Schistosoma mansoni, S. haematobium, and S. japonicum in vivo, but its drug disposition remains unknown. To bridge this gap, our study determined the basic pharmacokinetic (PK) parameters of a single oral dose (400 mg/kg of body weight) of OZ418 in uninfected mice. First, a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify OZ418 concentrations in mouse plasma was successfully developed and validated according to U.S. FDA guidelines. This method proved to be selective, accurate (93 to 103%), precise (5 to 16%), and devoid of significant matrix effects (90 to 102%) and provided excellent recovery (101 to 102%). A median peak concentration of 190 (range, 185 to 231) g/ml was reached at 2 h (2 to 3 h) posttreatment. A naive pooled noncompartmental PK analysis estimated a mean area under the plasma concentration-versus-time curve (AUC) of 9,303 g h/ml (7,039.2 to 11,908.5 g h/ml) and a half-life of 38.7 h (20 to 64.6 h). Thus, the OZ418 level in plasma remained well above its in vitro 50% inhibitory concentrations (IC 50 s) of 27.4 g/ml (adult S. mansoni worms at 72 h) for at least 75 h. Consistently, OZ418 degraded little in plasma at 37°C (<20% in 121 h) and weakly inhibited cytochrome P450 (CYP450) metabolism (IC 50 of 37 to 144 M). Our results provide a first insight into the disposition of OZ418, paving the way for further studies of its biological fate and effect.A dult trematodes of the genus Schistosoma parasitize blood vessels of the intestine (e.g., Schistosoma mansoni and S. japonicum) and bladder (S. haematobium), causing a chronic condition known as schistosomiasis (1). Being one of the major neglected tropical diseases, schistosomiasis affects over 200 million people and leads to chronic morbidity and, in some cases, mortality (1-5). Moreover, almost 800 million people, mostly in rural sub-Saharan Africa, are estimated to be at risk for Schistosoma infection (6). No vaccine is yet available, and changing human behavior and eliminating the intermediate host (snail) remain challenging (7-9). Thus, the current strategy relies on praziquantel for the treatment and control of schistosomiasis (10-12). This drug is safe, relatively inexpensive, and easy to distribute (13, 14). However, it lacks efficacy against developing juvenile stages of Schistosoma, and its widespread use raises grave concerns about emerging resistance (15)(16)(17)(18)(19)(20). In addition, praziquantel's mechanism of action still requires further elucidation to intelligently design active derivatives (21-26). Therefore, new antischistosomal pharmacophores have been greatly sought after in recent years (10,27,28).Inspired by the peroxide pharmacophore of the artem...

show abstract

Characterization of the two major CYP450 metabolites of ozonide (1,2,4-trioxolane) OZ277

Cited by 36 publications

References 14 publications

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

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

Anticancer Properties of Distinct Antimalarial Drug Classes

Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry

Contact Info

Product

Resources

About