Zhou, Hai-Shan; Hu, Lv-Bin; Zhang, Han; Shan, Wen-Xin; Wang, Yan; Li, Xue; Liu, Tian; Zhao, Jing; You, Qi-Dong; Jiang, Zheng-Yu published the artcile< Design, Synthesis, and Structure-Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors>, Quality Control of 6961-82-6, the main research area is indoline design synthesis cardioprotective Keap1 Nrf2 protein interaction inhibition.
The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target oxidative stress-related diseases, including cardiovascular diseases. Here, we describe the design, synthesis, and structure-activity relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2 PPI inhibitors. Comprehensive SAR anal. and thermodn.-guided optimization identified I as the most potent inhibitor in this series, with an IC50 of 22 nM in a competitive fluorescence polarization assay. Further evaluation indicated the proper drug-like properties of I. I dose-dependently upregulated genes and protein level of Nrf2 as well as its downstream markers and showed protective effects against lipopolysaccharide-induced injury in both H9c2 cardiac cells and mouse models. Collectively, we reported here a novel indoline-based Keap1-Nrf2 PPI inhibitor as a potential cardioprotective agent.
Journal of Medicinal Chemistry published new progress about Cardioprotective agents. 6961-82-6 belongs to class amides-buliding-blocks, and the molecular formula is C6H6ClNO2S, Quality Control of 6961-82-6.
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