1. Discovery and Modificationof in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: HitsIdentification and StructureâActivity Relationship Study.
- Author
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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, and Hao-Peng Sun
- Subjects
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DRUG development , *OXADIAZOLES , *TRANSCRIPTION factors , *ANTIOXIDANTS , *ANTI-inflammatory agents , *OXIDATIVE stress , *STRUCTURE-activity relationship in pharmacology , *IN vitro studies - Abstract
Inductionof phase II antioxidant enzymes by activation of Nrf2/ARE pathwayhas been recognized as a promising strategy for the regulation ofoxidative stress-related diseases. Herein we report our effort onthe discovery and optimization of Nrf2 activators with 1,2,4-oxadiazolecore. Screening of an in-house collection containing 7500 compoundsby ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecularsimilarity search by the combination of 2D fingerprint-based and 3Dshape-based search was applied to virtually screening the Chemdivcollection. Three derivatives with the same core were identified tohave better inductivity of Nrf2 than 1. The best hit 4was selected as starting point for structurally optimization,leading to a much more potent derivative 32. It in vitroupregulated gene and protein level of Nrf2 as well as its downstreammarkers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammationin the in vivo LPS-challenged mouse model. Our results provide a newchemotype as Nrf2-ARE activators which deserve further optimizationwith the aim to obtain active anti-inflammatory agents through Nrf2-AREpathway. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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