TY - JOUR
T1 - Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439
AU - Shackleford, David M.
AU - Chiu, Francis C.K.
AU - Katneni, Kasiram
AU - Blundell, Scott
AU - McLaren, Jenna
AU - Wang, Xiaofang
AU - Zhou, Lin
AU - Sriraghavan, Kamaraj
AU - Alker, André M.
AU - Hunziker, Daniel
AU - Scheurer, Christian
AU - Zhao, Qingjie
AU - Dong, Yuxiang
AU - Möhrle, Jörg J.
AU - Abla, Nada
AU - Matile, Hugues
AU - Wittlin, Sergio
AU - Vennerstrom, Jonathan L.
AU - Charman, Susan A.
N1 - Funding Information:
Financial support was received from the Medicines for Malaria Venture (J.L.V., S.A.C., S.W.) and the Nebraska Research Initiative (NRI, J.L.V.). The Centre for Drug Candidate Optimisation, Monash University (S.A.C) is part of the Monash University Technology Research Platform network and is supported in part by Therapeutic Innovation Australia (TIA) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. The expertise and advice from Dr. Armin Ruf (Roche) is gratefully acknowledged.
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/7/9
Y1 - 2021/7/9
N2 - 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.
AB - 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.
KW - OZ439 (artefenomel)
KW - cytochrome P450 inhibition
KW - cytochrome P450 metabolism
KW - malaria
KW - metabolite identification
KW - time-dependent inhibition
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U2 - 10.1021/acsinfecdis.1c00225
DO - 10.1021/acsinfecdis.1c00225
M3 - Article
C2 - 34101429
AN - SCOPUS:85109039776
SN - 2373-8227
VL - 7
SP - 1885
EP - 1893
JO - ACS infectious diseases
JF - ACS infectious diseases
IS - 7
ER -