Abstract
We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from T. gondii. The current work, through structure-activity relationship studies, led to the discovery of compounds (34 and 35) with improved characteristics over the starting inhibitor 1 in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds 34 and 35 were further demonstrated to be more effective than 1 in a mouse infection model and markedly reduced the amount of T. gondii in the brain, spleen, and peritoneal fluid, and 35 given at 20 mg/kg eliminated T. gondii from the peritoneal fluid.
Original language | English (US) |
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Pages (from-to) | 1184-1189 |
Number of pages | 6 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 6 |
Issue number | 12 |
DOIs | |
State | Published - Dec 10 2015 |
Externally published | Yes |
Keywords
- Toxoplasma gondii
- calcium-dependent protein kinase-1
- enzyme inhibitor
- structure-activity relationship studies
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry