Discovery and Structure-Activity Relationship Studies of Diazepine Derivatives as a New Class of Ferroptosis Inhibitors with Potent Efficacy in the Doxorubicin-Induced Cardiomyopathy Model.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, contributes to diverse pathological conditions. However, the clinical translation of ferroptosis inhibitors has been hampered by the limited efficacy or suboptimal pharmacokinetic profiles. Here, we report the discovery of diazepine derivatives as a new structural class of ferroptosis inhibitors. Through systematic structure-activity relationship optimization, we identified YL3147 as the most potent analogue, demonstrating exceptional cellular potency with an EC50 of 0.8 nM. Mechanistically, YL3147 functions as a radical-trapping antioxidant, directly halting the propagation of lipid peroxidation and thereby blocking ferroptosis. This compound also exhibits favorable drug-like pharmacokinetic properties. In vivo, YL3147 provided substantial protection against doxorubicin-induced cardiomyopathy in both acute and chronic murine models, with no detectable toxicity. Together, these findings establish YL3147 as a promising lead compound for the treatment of ferroptosis-related diseases, warranting further preclinical development.