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Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 Apr 13; Vol. 60 (7), pp. 2654-2668. Date of Electronic Publication: 2017 Jan 18. - Publication Year :
- 2017
-
Abstract
- 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 pK <subscript>a</subscript> and lower log D <subscript>7.4</subscript> 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 D <subscript>7.4</subscript> 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.
- Subjects :
- Adamantane administration & dosage
Adamantane blood
Adamantane pharmacology
Adamantane therapeutic use
Animals
Antimalarials administration & dosage
Antimalarials blood
Antimalarials pharmacology
Female
Male
Mice
Peroxides administration & dosage
Peroxides blood
Peroxides pharmacology
Rats
Structure-Activity Relationship
Adamantane analogs & derivatives
Antimalarials therapeutic use
Malaria drug therapy
Peroxides therapeutic use
Plasmodium berghei drug effects
Plasmodium falciparum drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28052200
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01586