title: Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase.
abstract: Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Qingzhang
authors.initials: Q
authors.lastname: Zhu
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D024982:Glycogen Phosphorylase, Muscle Form; D005941:Glucokinase