- 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
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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 analysis and thermodynamics-guided optimization identified 19a 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 19a. Compound 19a 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.
- 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
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supporting information
p. 11149 - 11168
(2020/11/09)
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- PROCESS FOR THE PREPARATION OF 2,4-DICHLORO-7H-PYRROLO[2,3H]QUINAZOLINE
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The invention relates to a method of preparing 2,4-dichloro-7H-pyrrolo[2,3-h]quinazoline (II): from 1H-pyrrolo[2,3-h]quinazoline-2,4-dione.
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Page/Page column 4; 5; 7; 8
(2010/03/02)
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- 7H-PYRROLO[2,3-H]QUINAZOLINE COMPOUNDS, THEIR USE AS mTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESIS
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A 7H-pyrrolo[2,3-h]quinazoline compound of the formula I wherein Ar, R1, R2, R7, R8, R9, R10, R11, R12, and n are as defined in the specification, and methods for maki
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Page/Page column 20
(2009/09/25)
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