title: Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure-Activity Relationship Study.
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.
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Xu
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Zhu
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Xu
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mei-Yang
authors.initials: MY
authors.lastname: Xi
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Jiang
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ming-Ye
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Meng-chen
authors.initials: MC
authors.lastname: Lu
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qi-Chao
authors.initials: QC
authors.lastname: Bao
authors.affiliation: §Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Wei
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.|∥Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Jin
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: ⊥National Engineering and Research Center for Target Drugs, Jiangsu Hengrui Medicine Co. Ltd., Lianyungang 222000, China.
authors.forename: Lian-Shan
authors.initials: LS
authors.lastname: Zhang
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.|⊥National Engineering and Research Center for Target Drugs, Jiangsu Hengrui Medicine Co. Ltd., Lianyungang 222000, China.
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.affiliation: †Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.|‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.|§Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hao-Peng
authors.initials: HP
authors.lastname: Sun
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D061745:Antioxidant Response Elements / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D051267:NF-E2-Related Factor 2; D010069:Oxadiazoles