2. Academic Validation
  3. Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action

Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action

  • ChemMedChem. 2016 Sep 20;11(18):1995-2014. doi: 10.1002/cmdc.201600298.
Christoph Boss 1,  Hamed Aissaoui 2,  Nathalie Amaral 2,  Aude Bauer 2,  Stephanie Bazire 2,  Christoph Binkert 2,  Reto Brun 3 4,  Cédric Bürki 2,  Claire-Lise Ciana 2 5,  Olivier Corminboeuf 2,  Stephane Delahaye 2,  Claire Dollinger 2,  Christoph Fischli 3 4,  Walter Fischli 2,  Alexandre Flock 2,  Marie-Céline Frantz 2 6,  Malory Girault 2,  Corinna Grisostomi 2,  Astrid Friedli 2,  Bibia Heidmann 2,  Claire Hinder 2,  Gael Jacob 2,  Amelie Le Bihan 2,  Sophie Malrieu 2,  Saskia Mamzed 2,  Aurelien Merot 2,  Solange Meyer 2,  Sabrina Peixoto 2,  Nolwenn Petit 2,  Romain Siegrist 2,  Julien Trollux 2,  Thomas Weller 2,  Sergio Wittlin 3 4
Affiliations

Affiliations

  • 1 Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland. [email protected].
  • 2 Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • 3 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.
  • 4 University of Basel, Petersplatz 1, 4001, Basel, Switzerland.
  • 5 Sygnature Discovery Ltd., BioCity, Pennyfoot Street, Nottingham, NG1 1GF, (UK).
  • 6 L'Oréal Research & Innovation, 1 Avenue Eugène Schueller, 93600, Aulnay-sous-Bois, France.
PMID: 27471138 DOI: 10.1002/cmdc.201600298
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

SCID mouse model; antimalarial drugs; malaria; phenotypic drug discovery; phenylalanine derivatives.

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