Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure–Activity Relationship Study
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
DOI:10.1021/acs.jmedchem.5b00170
日期:2015.7.23
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.