1. Academic Validation
  2. Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties

Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties

  • J Med Chem. 2016 Mar 10;59(5):2041-53. doi: 10.1021/acs.jmedchem.5b01641.
Sam Hofmans 1 Tom Vanden Berghe 2 Lars Devisscher 1 Behrouz Hassannia 2 Sophie Lyssens 1 Jurgen Joossens 1 Pieter Van Der Veken 1 Peter Vandenabeele 2 Koen Augustyns 1
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, University of Antwerp , Universiteitsplein 1, B-2610 Antwerp, Belgium.
  • 2 Molecular Signaling and Cell Death unit, VIB Inflammation Research Center , 9052 Ghent, Belgium.
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.

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