Research Papers:

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

Jun Zhang, Xue-Jiao Wang, Xin Liu, Yi Huan, Miao-Miao Yang, Zhu-Fang Shen, Wen-Qing Jia, Zhi Jing, Shu-Qing Wang, Wei-Ren Xu, Xian-Chao Cheng and Run-Ling Wang _

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Oncotarget. 2017; 8:20766-20783. https://doi.org/10.18632/oncotarget.15198

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Jun Zhang1, Xue-Jiao Wang1, Xin Liu1, Yi Huan2, Miao-Miao Yang2, Zhu-Fang Shen2, Wen-Qing Jia1, Zhi Jing1, Shu-Qing Wang1, Wei-Ren Xu3, Xian-Chao Cheng1, Run-Ling Wang1

1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China

2Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

3Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China

Correspondence to:

Xian-Chao Cheng, email: [email protected]

Run-Ling Wang, email: [email protected]

Keywords: PPARs, Type 2 diabetes mellitus, bioisosterism, docking analysis, molecular dynamic simulations

Received: December 28, 2016     Accepted: January 25, 2017     Published: February 08, 2017


Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.

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