Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439

David M. Shackleford, Francis C.K. Chiu, Kasiram Katneni, Scott Blundell, Jenna McLaren, Xiaofang Wang, Lin Zhou, Kamaraj Sriraghavan, André M. Alker, Daniel Hunziker, Christian Scheurer, Qingjie Zhao, Yuxiang Dong, Jörg J. Möhrle, Nada Abla, Hugues Matile, Sergio Wittlin, Jonathan L. Vennerstrom, Susan A. Charman

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug-drug interactions and support physiologically based pharmacokinetic (PBPK) modeling.

Original languageEnglish (US)
Pages (from-to)1885-1893
Number of pages9
JournalACS infectious diseases
Issue number7
StatePublished - Jul 9 2021


  • OZ439 (artefenomel)
  • cytochrome P450 inhibition
  • cytochrome P450 metabolism
  • malaria
  • metabolite identification
  • time-dependent inhibition

ASJC Scopus subject areas

  • Infectious Diseases


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