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Discovery and characterization of ACT-451840 : an antimalarial drug with a novel mechanism of action

Boss, Christoph and Aissaoui, Hamed and Amaral, Nathalie and Bauer, Aude and Bazire, Stephanie and Binkert, Christoph and Brun, Reto and Bürki, Cédric and Ciana, Claire-Lise and Corminboeuf, Olivier and Delahaye, Stephane and Dollinger, Claire and Fischli, Christoph and Fischli, Walter and Flock, Alexandre and Frantz, Marie-Céline and Girault, Malory and Grisostomi, Corinna and Friedli, Astrid and Heidmann, Bibia and Hinder, Claire and Jacob, Gael and Le Bihan, Amelie and Malrieu, Sophie and Mamzed, Saskia and Merot, Aurelien and Meyer, Solange and Peixoto, Sabrina and Petit, Nolwenn and Siegrist, Romain and Trollux, Julien and Weller, Thomas and Wittlin, Sergio. (2016) Discovery and characterization of ACT-451840 : an antimalarial drug with a novel mechanism of action. ChemMedChem, 11 (18). pp. 1995-2014.

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Official URL: http://edoc.unibas.ch/44584/

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Abstract

More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Wittlin, Sergio
Item Type:Article, refereed
ISSN:1860-7179
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Dec 2016 15:18
Deposited On:08 Dec 2016 15:18

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