1. Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase.
- Author
-
Zhang L, Chen X, Liu J, Zhu Q, Leng Y, Luo X, Jiang H, and Liu H
- Subjects
- Animals, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Glycogen Phosphorylase, Muscle Form metabolism, Humans, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents chemistry, Models, Molecular, Molecular Structure, Rabbits, Structure-Activity Relationship, Drug Discovery, Enzyme Inhibitors pharmacology, Glucokinase metabolism, Glycogen Phosphorylase, Muscle Form antagonists & inhibitors, Hypoglycemic Agents pharmacology
- 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., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF