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Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action
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
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
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.
Keywords:antimalarial drugs  malaria  phenotypic drug discovery  phenylalanine derivatives  SCID mouse model
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