Glucokinase Activator Design, Synthesis And Structure-activity Relationship Studies

Glucokinase(GK), a rate-limiting enzyme in glucose metabolism, plays a key role in the maintaining glucose homeostasis as a glucose sensor in many vertebrates including humans. The conformation of GK changes into the active form, when the glucokinase activator binds to the allosteric site, which enhances the catalytic activity of GK, increases the glucose metabolism and reduces the blood glucose levels. GK is 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, the character of the ligand structure and the binding model, the target compounds were designed as GK activators. Then the designed compounds were synthesized, activity evaluated and SAR analysised, which can further guide the novel GKAs design.Thirty-eight unreported compounds were synthesized, in which seventeen unreported target compounds were obtained and identified by H NMR and MS. The target compounds were evaluated in vitro, several compounds exhibited potent activity.The activity data and structure-activity relationships of synthesized compounds offered useful information for the design and synthesis of new compounds.