title: Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists.
abstract: 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.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huan
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Miao-Miao
authors.initials: MM
authors.lastname: Yang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Zhu-Fang
authors.initials: ZF
authors.lastname: Shen
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Wen-Qing
authors.initials: WQ
authors.lastname: Jia
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Jing
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Wei-Ren
authors.initials: WR
authors.lastname: Xu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xian-Chao
authors.initials: XC
authors.lastname: Cheng
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Run-Ling
authors.initials: RL
authors.lastname: Wang
mesh_terms: D015195:Drug Design; D007004:Hypoglycemic Agents / Q000737:chemistry*; D062105:Molecular Docking Simulation; D047492:Peroxisome Proliferator-Activated Receptors / Q000037:antagonists & inhibitors*; D045162:Thiazolidinediones / Q000737:chemistry*
chemical_list: D007004:Hypoglycemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones
keywords: PPARs; Type 2 diabetes mellitus; bioisosterism; docking analysis; molecular dynamic simulations