1. Investigating Sulfoxide-to-Sulfone Conversion as a Prodrug Strategy for a Phosphatidylinositol 4-Kinase Inhibitor in a Humanized Mouse Model of Malaria
- Author
-
Christel Brunschwig, Tanya Paquet, Efrem Abay, Mathew Njoroge, Liezl Gibhard, Lubbe Wiesner, Leslie J. Street, Dale Taylor, Kelly Chibale, Sergio Wittlin, Nina Lawrence, and Gregory S. Basarab
- Subjects
Male ,0301 basic medicine ,Erythrocytes ,Metabolite ,Plasmodium falciparum ,030106 microbiology ,Gene Expression ,Mice, SCID ,Pharmacology ,Parasitemia ,Sulfone ,Antimalarials ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Pharmacokinetics ,Mice, Inbred NOD ,In vivo ,Animals ,Humans ,Experimental Therapeutics ,Prodrugs ,Pharmacology (medical) ,Sulfones ,Malaria, Falciparum ,1-Phosphatidylinositol 4-Kinase ,Biotransformation ,Active metabolite ,Dose-Response Relationship, Drug ,biology ,Sulfoxide ,Prodrug ,biology.organism_classification ,Disease Models, Animal ,Treatment Outcome ,Infectious Diseases ,chemistry ,Pyrazines ,Sulfoxides - Abstract
The; in vivo; antimalarial efficacies of two phosphatidylinositol 4-kinase (PI4K) inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2Rγ; null; (NSG) murine malaria disease model of; Plasmodium falciparum; infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure with oral dosing. Both compounds had similar efficacy (90% effective dose [ED; 90; ], 0.1 mg kg; -1; of body weight) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to sulfone, with sulfone identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria.
- Published
- 2018
- Full Text
- View/download PDF