Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy.
- Baragaña B Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Norcross NR Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Wilson C Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Porzelle A Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Hallyburton I Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Grimaldi R Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Osuna-Cabello M Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Norval S Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Riley J Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Stojanovski L Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Simeons FR Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Wyatt PG Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Delves MJ Cell and Molecular Biology, Department of Life Sciences, Imperial College , London, SW7 2AZ, U.K.
- Meister S School of Medicine, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
- Duffy S Eskitis Institute, Griffith University , Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia.
- Avery VM Eskitis Institute, Griffith University , Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia.
- Winzeler EA School of Medicine, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
- Sinden RE Cell and Molecular Biology, Department of Life Sciences, Imperial College , London, SW7 2AZ, U.K.
- Wittlin S Swiss Tropical and Public Health Institute, Swiss TPH, Socinstrasse 57, 4051 Basel, Switzerland.
- Frearson JA Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Gray DW Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Fairlamb AH Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Waterson D Medicines for Malaria Venture , International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
- Campbell SF Medicines for Malaria Venture , International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
- Willis P Medicines for Malaria Venture , International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
- Read KD Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- Gilbert IH Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
- 2016-09-16
Published in:
- Journal of medicinal chemistry. - 2016
Animals
Antimalarials
Disease Models, Animal
Drug Discovery
Malaria
Mice
Molecular Structure
Plasmodium falciparum
Quinolines
Structure-Activity Relationship
English
The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1021/acs.jmedchem.6b00723
- PMID 27631715
- Persistent URL
- https://sonar.ch/global/documents/51272
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