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Medicinal Chemistry Approaches for Glucokinase Activation to Treat Type 2 Diabetes

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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.

Keywords: Glucokinase; glucose homeostasis; glucose-lowering effect; kinase activators; phosphorylation; type 2 diabetes

Document Type: Research Article


Affiliations: New Drug Discovery, Matrix Laboratories Limited, Anrich Industrial Estate, Bollaram, Jinnaram Mandal, Medak District, Andhra Pradesh 502 325, India.

Publication date: October 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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