Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 14, Pages 5419-5436Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00170
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Funding
- National Natural Science Foundation of China [81230078, 81202463, 91129732, 81273375]
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2014ZX09507002-005-015, 2013ZX09402102-001-005, 2010ZX09401-401]
- Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) [20130096110002]
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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.
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