title: Design, synthesis, and activity evaluation of GK/PPARγ dual-target-directed ligands as hypoglycemic agents.
abstract: Based on the multi-target strategy to treat type 2 diabetes mellitus (T2DM), glucokinase/peroxisome proliferator-activated receptor γ (GK/PPARγ) dual-target molecules were constructed by the rational combination of pharmacophores from known GK activators and PPARγ agonists. A series of dual-target agents were designed and synthesized, and their capacities to induce GK and PPARγ transcriptional activity were evaluated. Three of these compounds showed particularly high potency toward GK, moderate activity toward PPARγ, and their structure-activity relationships were preliminarily analyzed. The putative binding modes of one of the most promising compounds were also explored by molecular docking simulations with GK and PPARγ.
authors.affiliation: Capital Normal University, 105 North Xisanhuan Road, Beijing, 100048 (China).
authors.forename: Jianxun
authors.initials: J
authors.lastname: Lu
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.forename: Yi
authors.initials: Y
authors.lastname: Huan
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Li
authors.forename: Lijing
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Shen
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Hu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Feng
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D005941:Glucokinase
keywords: PPAR; activators; agonists; dual targeting; glucokinase; receptors