Discovery of Propionic Acid Derivatives with a 5-THIQ Core as Potent and Orally Bioavailable Keap1-Nrf2 Protein-Protein Interaction Inhibitors for Acute Kidney Injury.

Keap1 plays a crucial role in regulating the Nrf2-mediated cytoprotective response and is increasingly targeted for oxidative stress-related diseases. Using small molecules to disrupt the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as a new strategy for developing Nrf2 activators. Through extensive structure-activity relationship studies, we identified compound , which features a unique 5-tetrahydroisoquinoline scaffold and acts as a potent inhibitor of the Keap1-Nrf2 PPI. Compound exhibited significant inhibitory activity (IC = 16.0 nM) and tight Keap1 binding affinity ( = 3.07 nM), along with acceptable oral bioavailability ( = 20%). Notably, enhanced antioxidant defenses in HK-2 renal tubular epithelial cells and significantly reduced plasma creatinine and blood urea nitrogen levels in acute kidney injury (AKI) mice. These findings collectively position compound as a promising candidate for the treatment of AKI.