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

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 imp...

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Autores principales: Zhang, Jun, Wang, Xue-Jiao, Liu, Xin, Huan, Yi, Yang, Miao-Miao, Shen, Zhu-Fang, Jia, Wen-Qing, Jing, Zhi, Wang, Shu-Qing, Xu, Wei-Ren, Cheng, Xian-Chao, Wang, Run-Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400543/
https://www.ncbi.nlm.nih.gov/pubmed/28186999
http://dx.doi.org/10.18632/oncotarget.15198
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author Zhang, Jun
Wang, Xue-Jiao
Liu, Xin
Huan, Yi
Yang, Miao-Miao
Shen, Zhu-Fang
Jia, Wen-Qing
Jing, Zhi
Wang, Shu-Qing
Xu, Wei-Ren
Cheng, Xian-Chao
Wang, Run-Ling
author_facet Zhang, Jun
Wang, Xue-Jiao
Liu, Xin
Huan, Yi
Yang, Miao-Miao
Shen, Zhu-Fang
Jia, Wen-Qing
Jing, Zhi
Wang, Shu-Qing
Xu, Wei-Ren
Cheng, Xian-Chao
Wang, Run-Ling
author_sort Zhang, Jun
collection PubMed
description 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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spelling pubmed-54005432017-05-03 Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists Zhang, Jun Wang, Xue-Jiao Liu, Xin Huan, Yi Yang, Miao-Miao Shen, Zhu-Fang Jia, Wen-Qing Jing, Zhi Wang, Shu-Qing Xu, Wei-Ren Cheng, Xian-Chao Wang, Run-Ling Oncotarget Research Paper 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. Impact Journals LLC 2017-02-08 /pmc/articles/PMC5400543/ /pubmed/28186999 http://dx.doi.org/10.18632/oncotarget.15198 Text en Copyright: © 2017 Zhang et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Zhang, Jun
Wang, Xue-Jiao
Liu, Xin
Huan, Yi
Yang, Miao-Miao
Shen, Zhu-Fang
Jia, Wen-Qing
Jing, Zhi
Wang, Shu-Qing
Xu, Wei-Ren
Cheng, Xian-Chao
Wang, Run-Ling
Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists
title Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists
title_full Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists
title_fullStr Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists
title_full_unstemmed Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists
title_short Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists
title_sort design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as ppars agonists
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400543/
https://www.ncbi.nlm.nih.gov/pubmed/28186999
http://dx.doi.org/10.18632/oncotarget.15198
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