Discovery of Novel, Drug-Like Ferroptosis Inhibitors with in Vivo Efficacy

Ferroptosis is an
iron-catalyzed, nonapoptotic form of regulated
necrosis that results in oxidative lipid damage in cell membranes
that can be inhibited by the radical-trapping antioxidant Ferrostatin-1
(Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited
ferroptosis potently but suffered from solubility issues. In this
paper, we report the synthesis of a more stable and readily soluble
series of Fer-1 analogues that potently inhibit ferroptosis. The most
promising compounds (37, 38, and 39) showed an improved protection compared to Fer-1 against multiorgan
injury in mice. No toxicity was observed in mice after daily injection
of 39 (UAMC-3203) for 4 weeks. UAMC-3203 inserts rapidly in a phospholipid bilayer in silico, which aligns
with the current understanding of the mechanism of action of these
compounds. In conclusion, these analogues have superior properties
compared to Fer-1, show in vivo efficacy, and represent novel lead
compounds with therapeutic potential in relevant ferroptosis-driven
disease models.