- Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action
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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.
- Boss, Christoph,Aissaoui, Hamed,Amaral, Nathalie,Bauer, Aude,Bazire, Stephanie,Binkert, Christoph,Brun, Reto,Bürki, Cédric,Ciana, Claire-Lise,Corminboeuf, Olivier,Delahaye, Stephane,Dollinger, Claire,Fischli, Christoph,Fischli, Walter,Flock, Alexandre,Frantz, Marie-Céline,Girault, Malory,Grisostomi, Corinna,Friedli, Astrid,Heidmann, Bibia,Hinder, Claire,Jacob, Gael,Le Bihan, Amelie,Malrieu, Sophie,Mamzed, Saskia,Merot, Aurelien,Meyer, Solange,Peixoto, Sabrina,Petit, Nolwenn,Siegrist, Romain,Trollux, Julien,Weller, Thomas,Wittlin, Sergio
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supporting information
p. 1995 - 2014
(2016/10/22)
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- PIPERAZINES AS ANTIMALARIAL AGENTS
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The invention relates to piperazine derivatives of Formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including pharmaceutical compositions containing one or more of
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Page/Page column 18
(2011/08/03)
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