Design, Synthesis And Sar Analysis Of Glucokinase Activators

Glucokinase(GK),a rate-limiting enzyme in glucose metabolism,plays a key role in maintaining glucose homeostasis due to its dual mechanism of regulating islet insulin release and enhancing hepatic glucose disposal.The conformation of GK can not change back to the inactive form,when the glucokinase activator binds to the allosteric site,resulting in the enhancement,of the catalytic activity of GK.GK has been becoming an important target to treat type 2 diabetes.The study of small molecule activators based on GK is very active, which is hopeful to develop a novel treatment for diabetes.Based on the known 3D-structure of GK-ligand complex and the character of the ligand structure and the binding model,structural modification and optimization for gentistic derivatives——LYQ127 and compound 23,which show a GK activity,was conducted. Derivatives of orotic amides were designed and synthesized as a new type of GK activators.34 target compounds,including 29 gentisic amides and 5 orotic amides,which were unreported,were synthesized.All the target compounds were identified by ~1H-NMR and ESI-MS.The 29 gentisic amides were evaluated in vitro.Several compounds exhibited a similar activity as the positive drug or showed a better one.The activity data and structure-activity relationships of synthesized compounds offered useful information for the design and synthesis of new lead compound of GK activators.