Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase

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.

Sixty-two hybrid compounds targeting both glycogen phosphorylase and glucokinase were designed, synthesized, and evaluated. The possible binding modes of two promising compounds were explored by docking simulation.Figure optionsDownload as PowerPoint slideHighlights
► We hypothesized that some reported GK activators or GP inhibitors may play a dual role on these two targets.
► Sixty-two hybrid compounds were designed by structure-assisted and ligand-based strategies.
► Two novel compounds (1j, 6g) displayed dual actions to enzymes GP and GK.
►  The possible binding modes of compounds 1j and 6g were explored by molecular docking simulation.