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 56, which features a unique 5-tetrahydroisoquinoline scaffold and acts as a potent inhibitor of the Keap1–Nrf2 PPI. Compound 56 exhibited significant inhibitory activity (IC50 = 16.0 nM) and tight Keap1 binding affinity (Kd = 3.07 nM), along with acceptable oral bioavailability (F = 20%). Notably, 56 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 56 as a promising candidate for the treatment of AKI.