title: Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties.
abstract: Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high-throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Sam
authors.initials: S
authors.lastname: Hofmans
authors.affiliation: Molecular Signaling and Cell Death unit, VIB Inflammation Research Center , 9052 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Vanden Berghe
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Lars
authors.initials: L
authors.lastname: Devisscher
authors.affiliation: Molecular Signaling and Cell Death unit, VIB Inflammation Research Center , 9052 Ghent, Belgium.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Hassannia
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lyssens
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Der Veken
authors.affiliation: Molecular Signaling and Cell Death unit, VIB Inflammation Research Center , 9052 Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003514:Cyclohexylamines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D003514:Cyclohexylamines; D010655:Phenylenediamines; C573944:ferrostatin-1