Identification of YH-GKA, a novel benzamide glucokinase activator as therapeutic candidate for type 2 diabetes mellitus.

Glucokinase activator is expectedly associated with a dual mechanism for lowering blood glucose concentration by the enhancement of glucose uptake in the liver and insulin secretion from pancreatic beta cell. Therefore, glucokinase has been an attractive target for anti-diabetic therapy. Novel benzamide derivatives were synthesized and tested using in vitro assays by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC(50) of 70 nM and glucose area under the curve reduction of 29.6% at 50 mg/kg in an oral glucose tolerance test. In a subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. Overall, YH-GKA is a promising candidate for the therapy of type 2 diabetes mellitus.