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Investigating Sulfoxide-to-Sulfone Conversion as a Prodrug Strategy for a Phosphatidylinositol 4-Kinase Inhibitor in a Humanized Mouse Model of Malaria
- Source :
- Antimicrobial Agents and Chemotherapy. 62
- Publication Year :
- 2018
- Publisher :
- American Society for Microbiology, 2018.
-
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.
- 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
Subjects
Details
- ISSN :
- 10986596 and 00664804
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy
- Accession number :
- edsair.doi.dedup.....899015955c47e27829028de951fa25b5