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There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine\u2010based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT\u2010451840 [(<jats:italic>S<\/jats:italic>,<jats:italic>E<\/jats:italic>)\u2010<jats:italic>N<\/jats:italic>\u2010(4\u2010(4\u2010acetylpiperazin\u20101\u2010yl)benzyl)\u20103\u2010(4\u2010(<jats:italic>tert<\/jats:italic>\u2010butyl)phenyl)\u2010<jats:italic>N<\/jats:italic>\u2010(1\u2010(4\u2010(4\u2010cyanobenzyl)piperazin\u20101\u2010yl)\u20101\u2010oxo\u20103\u2010phenylpropan\u20102\u2010yl)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\u2005vivo pharmacological efficacy.<\/jats:p>","DOI":"10.1002\/cmdc.201600298","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T04:18:50Z","timestamp":1470197930000},"page":"1995-2014","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Discovery and Characterization of ACT\u2010451840: an Antimalarial Drug with a Novel Mechanism of Action"],"prefix":"10.1002","volume":"11","author":[{"given":"Christoph","family":"Boss","sequence":"first","affiliation":[{"name":"Actelion Pharmaceuticals Ltd. 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