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

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

  • Boss C Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland. christoph.boss@actelion.com.
  • Aissaoui H Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Amaral N Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Bauer A Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Bazire S Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Binkert C Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Brun R Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.
  • Bürki C Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Ciana CL Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Corminboeuf O Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Delahaye S Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Dollinger C Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Fischli C Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.
  • Fischli W Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Flock A Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Frantz MC Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Girault M Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Grisostomi C Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Friedli A Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Heidmann B Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Hinder C Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Jacob G Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Le Bihan A Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Malrieu S Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Mamzed S Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Merot A Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Meyer S Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Peixoto S Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Petit N Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Siegrist R Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Trollux J Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Weller T Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
  • Wittlin S Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.
Show more…
  • 2016-07-30
Published in:
  • ChemMedChem. - 2016
SCID mouse model
antimalarial drugs
malaria
phenotypic drug discovery
phenylalanine derivatives
Acrylamides
Antimalarials
Dose-Response Relationship, Drug
Drug Discovery
Malaria
Molecular Structure
Parasitic Sensitivity Tests
Piperazines
Plasmodium falciparum
Structure-Activity Relationship
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/92512
Statistics
Document views: 41 File downloads: