title: Discovery of novel urea derivatives as dual-target hypoglycemic agents that activate glucokinase and PPARγ.
abstract: Motivated by the discovery of a potential ligand that activates both glucokinase (GK) and perioxisome proliferator-activated receptor-γ (PPARγ), this work presents the rational design and synthesis of a series of novel urea derivatives as potent dual-target ligands of GK and PPARγ. The derivatives obtained, particularly compounds 14j, 14m, 15g, 15j, and 15s, showed relatively high enzyme activity and moderate blood glucose-lowering efficacy in normal ICR mice (GK activation fold >1.7, PPARγ activation percentage >38.8%, relative to rosiglitazone). The discovery of a dual-acting agent may provide an effective approach for treating type 2 diabetes mellitus.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: liyongqiang@imm.ac.cn.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Tian
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Aifang
authors.initials: A
authors.lastname: Qin
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Lianchao
authors.initials: L
authors.lastname: Huo
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Shen
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Song
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: fengzhq@imm.ac.cn.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Feng
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004789:Enzyme Activation; D005941:Glucokinase / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008813:Mice, Inbred ICR; D047495:PPAR gamma / Q000819:agonists*; D021241:Spectrometry, Mass, Electrospray Ionization; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D014508:Urea; D005941:Glucokinase
keywords: Dual-target; Glucokinase activator; PPARγ; Type 2 diabetes; Urea derivatives