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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5419-5436
Number of pages18
JournalJournal of medicinal chemistry
Volume58
Issue number14
DOIs
StatePublished - Jul 23 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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