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J Med Chem. 2017 Apr 13;60(7):2654-2668. doi: 10.1021/acs.jmedchem.6b01586. Epub 2017 Jan 18.

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

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College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.
University of Basel , CH-4003 Basel, Switzerland.
Basilea Pharmaceutica Ltd. , Grenzacherstrasse 487, CH-4058 Basel, Switzerland.
F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.


Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

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