Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 18, Pages 7572-7579Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01156
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Funding
- Medicines for Malaria Venture (MMV)
- South African Technology Innovation Agency (TIA) [MMV09/0002]
- University of Cape Town
- South African Medical Research Council
- South African Research Chairs Initiative of the Department of Science and Technology
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Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.
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