Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties

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.