Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 2, Issue 11, Pages 840-844Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml2001517
Keywords
TCAMS; Tres Cantos Anti-Malarial Set; malaria; cyclopropyl; carboxamide; triazole; oral bioavailability; in vivo activity; murine; Plasmodium falciparum; Medicines for Malaria Venture
Categories
Funding
- Medicines for Malaria Venture (MMV)
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Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a standard Plasmodium falciparum in vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P.falciparum murine model.
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