Medicinal Chemistry Approaches for Glucokinase Activation to Treat Type 2 Diabetes

Type 2 Diabetes (T2D), characterized by elevated levels of blood glucose is a complex disease mainly caused by defects in hepatic glucose balance and the failure of pancreatic β-cells to secrete enough insulin to overcome insulin resistance. Glucokinase (GK) is a member of hexokinase family of enzymes that are responsible for the phosphorylation of glucose to glucose-6-phosphate for further utilization in cells. It plays a key role in glucose homeostasis in cells that express this enzyme, such as β-cells and hepatocytes. It promotes glycogen synthesis in the liver and glucose-sensitive insulin release in the β-cell. While hypoglycemia due to the increased insulin secretion could be a potential concern it was hypothesized that a GK activator with optimized properties would be able to both blunt the postprandial glucose excursion and lower the fasting blood glucose in T2D patients. As a result of intensive medicinal chemistry efforts a number of small molecules have been discovered as GK activators many of which showed antidiabetic effects in animal models of T2D. Some of these activators have advanced into human clinical studies. With the promising preclinical data in hand, GK activators represent a promising and new treatment option for T2D.