1. Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action
- Author
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Julien Trollux, Aurelien Merot, Hamed Aissaoui, Christoph Binkert, Alexandre Flock, Stephane Delahaye, Christoph Fischli, Amélie Le Bihan, Christoph Boss, Aude Bauer, Reto Brun, Claire-Lise Ciana, Malory Girault, Sergio Wittlin, Sabrina Peixoto, Sophie Malrieu, Olivier Corminboeuf, Thomas Weller, Claire Hinder, Romain Siegrist, Saskia Mamzed, Claire Dollinger, Marie-Céline Frantz, Walter Fischli, Nolwenn Petit, Solange Meyer, Corinna Grisostomi, Astrid Friedli, Stephanie Bazire, Nathalie Amaral, Bibia Heidmann, Gael Jacob, and Cédric Bürki
- Subjects
0301 basic medicine ,Drug ,Phenotypic screening ,media_common.quotation_subject ,Population ,Plasmodium falciparum ,Biology ,Pharmacology ,01 natural sciences ,Biochemistry ,Piperazines ,03 medical and health sciences ,Antimalarials ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,Drug Discovery ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Artemisinin ,education ,media_common ,education.field_of_study ,Acrylamides ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,medicine.disease ,0104 chemical sciences ,Malaria ,030104 developmental biology ,Mechanism of action ,Molecular Medicine ,Classical pharmacology ,medicine.symptom ,Drug metabolism ,medicine.drug - 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.
- Published
- 2016