Discovery of novel 5-phenyl-1H-pyrrole-2-carboxylic acids as Keap1-Nrf2 inhibitors for acute lung injury treatment.

Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a K of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.