title: Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.
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.
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland. christoph.boss@actelion.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Hamed
authors.initials: H
authors.lastname: Aissaoui
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Amaral
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Aude
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bazire
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Binkert
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.|University of Basel, Petersplatz 1, 4001, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Bürki
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.|Sygnature Discovery Ltd., BioCity, Pennyfoot Street, Nottingham, NG1 1GF, (UK).
authors.forename: Claire-Lise
authors.initials: CL
authors.lastname: Ciana
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Corminboeuf
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Stephane
authors.initials: S
authors.lastname: Delahaye
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Dollinger
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.|University of Basel, Petersplatz 1, 4001, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Fischli
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Flock
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.|L'Oréal Research & Innovation, 1 Avenue Eugène Schueller, 93600, Aulnay-sous-Bois, France.
authors.forename: Marie-Céline
authors.initials: MC
authors.lastname: Frantz
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Malory
authors.initials: M
authors.lastname: Girault
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Corinna
authors.initials: C
authors.lastname: Grisostomi
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Friedli
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Bibia
authors.initials: B
authors.lastname: Heidmann
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Hinder
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Gael
authors.initials: G
authors.lastname: Jacob
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Amelie
authors.initials: A
authors.lastname: Le Bihan
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Malrieu
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Saskia
authors.initials: S
authors.lastname: Mamzed
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Aurelien
authors.initials: A
authors.lastname: Merot
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Solange
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Peixoto
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Petit
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Romain
authors.initials: R
authors.lastname: Siegrist
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Trollux
authors.affiliation: Actelion Pharmaceuticals Ltd., Drug Discovery & Preclinical Development, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.|University of Basel, Petersplatz 1, 4001, Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D008288:Malaria / Q000188:drug therapy*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C000619473:ACT-451840; D000178:Acrylamides; D000962:Antimalarials; D010879:Piperazines
keywords: SCID mouse model; antimalarial drugs; malaria; phenotypic drug discovery; phenylalanine derivatives