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Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action
Author(s) -
Boss Christoph,
Aissaoui Hamed,
Amaral Nathalie,
Bauer Aude,
Bazire Stephanie,
Binkert Christoph,
Brun Reto,
Bürki Cédric,
Ciana ClaireLise,
Corminboeuf Olivier,
Delahaye Stephane,
Dollinger Claire,
Fischli Christoph,
Fischli Walter,
Flock Alexandre,
Frantz MarieCéline,
Girault Malory,
Grisostomi Corinna,
Friedli Astrid,
Heidmann Bibia,
Hinder Claire,
Jacob Gael,
Le Bihan Amelie,
Malrieu Sophie,
Mamzed Saskia,
Merot Aurelien,
Meyer Solange,
Peixoto Sabrina,
Petit Nolwenn,
Siegrist Romain,
Trollux Julien,
Weller Thomas,
Wittlin Sergio
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600298
Subject(s) - drug , malaria , artemisinin , pharmacology , mechanism of action , drug resistance , plasmodium falciparum , pharmacokinetics , population , drug action , in vivo , medicine , biology , microbiology and biotechnology , in vitro , biochemistry , genetics , immunology , environmental health
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.