Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action |
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| Authors: | Dr Christoph Boss Dr Hamed Aissaoui Nathalie Amaral Aude Bauer Stephanie Bazire Dr Christoph Binkert Prof Reto Brun Dr Cédric Bürki Dr Claire‐Lise Ciana Dr Olivier Corminboeuf Stephane Delahaye Claire Dollinger Christoph Fischli Dr Walter Fischli Alexandre Flock Dr Marie‐Céline Frantz Malory Girault Dr Corinna Grisostomi Astrid Friedli Dr Bibia Heidmann Claire Hinder Gael Jacob Amelie Le?Bihan Sophie Malrieu Dr Saskia Mamzed Aurelien Merot Dr Solange Meyer Dr Sabrina Peixoto Nolwenn Petit Dr Romain Siegrist Julien Trollux Dr Thomas Weller Dr Sergio Wittlin |
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| Affiliation: | 1. Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Allschwil, Switzerland;2. Swiss Tropical and Public Health Institute, Basel, Switzerland;3. University of Basel, Basel, Switzerland;4. Sygnature Discovery Ltd., BioCity, Nottingham, (UK);5. L'Oréal Research & Innovation, Aulnay-sous-Bois, France |
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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. |
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| Keywords: | antimalarial drugs malaria phenotypic drug discovery phenylalanine derivatives SCID mouse model |
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