Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure鈥揂ctivity Relationship Study

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• 作者：Li-Li Xu ; Jun-Feng Zhu ; Xiao-Li Xu ; Jie Zhu ; Li Li ; Mei-Yang Xi ; Zheng-Yu Jiang ; Ming-Ye Zhang ; Fang Liu ; Meng-chen Lu ; Qi-Chao Bao ; Qi Li ; Chao Zhang ; Jin-Lian Wei ; Xiao-Jin Zhang ; Lian-Shan Zhang ; Qi-Dong You ; Hao-Peng Sun
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5419-5436
• 全文大小：860K
• ISSN：1520-4804

文摘

Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress-related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of an in-house collection containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination of 2D fingerprint-based and 3D shape-based search was applied to virtually screening the Chemdiv collection. Three derivatives with the same core were identified to have better inductivity of Nrf2 than 1. The best hit 4 was selected as starting point for structurally optimization, leading to a much more potent derivative 32. It in vitro upregulated gene and protein level of Nrf2 as well as its downstream markers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammation in the in vivo LPS-challenged mouse model. Our results provide a new chemotype as Nrf2-ARE activators which deserve further optimization with the aim to obtain active anti-inflammatory agents through Nrf2-ARE pathway.