title: Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS).
abstract: 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.
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Rueda
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Castellote
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Castro-Pichel
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Chaparro
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de la Rosa
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Perez
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Mariola
authors.initials: M
authors.lastname: Gordo
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Jimenez-Diaz
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Albane
authors.initials: A
authors.lastname: Kessler
authors.affiliation: Medicines for Malaria Venture, ICC, Route de Pre-Bois, PO Box 1826, 1215 Geneva 15, Switzerland.
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Maria Santos
authors.initials: MS
authors.lastname: Martinez
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Fernandez
keywords: Medicines for Malaria Venture; Plasmodium falciparum; TCAMS; Tres Cantos Anti-Malarial Set; carboxamide; cyclopropyl; in vivo activity; malaria; murine; oral bioavailability; triazole