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

Autor:	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.; University of Basel, Petersplatz 1, 4001, 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.; Sygnature Discovery Ltd., BioCity, Pennyfoot Street, Nottingham, NG1 1GF, (UK)., 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.; University of Basel, Petersplatz 1, 4001, 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.; L'Oréal Research & Innovation, 1 Avenue Eugène Schueller, 93600, Aulnay-sous-Bois, France., 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.; University of Basel, Petersplatz 1, 4001, Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	ChemMedChem [ChemMedChem] 2016 Sep 20; Vol. 11 (18), pp. 1995-2014. Date of Electronic Publication: 2016 Jul 29.
DOI:	10.1002/cmdc.201600298
Abstrakt:	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. (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze:	MEDLINE
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