Abstract
The search for innovative and clinically-differentiated medicines for the treatment of type 2 diabetes is an active area of research for pharmaceutical companies. The discovery of allosteric Glucokinase (GK) activators in 2003 represents the first time a pharmaceutical agent was used to directly augment the actions of an enzyme by increasing its maximal velocity and substrate affinity. This discovery, coupled with translational medicine which has shown that inactivating and activating GK mutations cause glycemic diseases, has triggered an intensive medicinal chemistry effort in the field of glucokinase activators (GKAs). The antidiabetic effects of GK activators observed in animal models support the notion that these agents act to both augment insulin release from pancreatic β-cells and suppress hepatic glucose production in the liver. This review describes the unprecedented task of optimizing small molecules in order to affect the appropriate changes in the kinetic parameters of an enzyme. In addition, a pharmacophore model for the various classes of glucokinase activators that have been described in the literature will be presented. Overall, the available data suggests that potent glucokinase activators with the desired effects on the kinetic properties of the enzyme can be designed to achieve strong and persistent antidiabetic effects. GK activators thus represent a promising new treatment for type 2 diabetes.
Keywords: Antidiabetic agents, type 2 diabetes, allosteric activator, glucokinase activators
Current Topics in Medicinal Chemistry
Title: Glucokinase Activators for the Potential Treatment of Type 2 Diabetes
Volume: 8 Issue: 17
Author(s): J. Grimsby, S. J. Berthel and R. Sarabu
Affiliation:
Keywords: Antidiabetic agents, type 2 diabetes, allosteric activator, glucokinase activators
Abstract: The search for innovative and clinically-differentiated medicines for the treatment of type 2 diabetes is an active area of research for pharmaceutical companies. The discovery of allosteric Glucokinase (GK) activators in 2003 represents the first time a pharmaceutical agent was used to directly augment the actions of an enzyme by increasing its maximal velocity and substrate affinity. This discovery, coupled with translational medicine which has shown that inactivating and activating GK mutations cause glycemic diseases, has triggered an intensive medicinal chemistry effort in the field of glucokinase activators (GKAs). The antidiabetic effects of GK activators observed in animal models support the notion that these agents act to both augment insulin release from pancreatic β-cells and suppress hepatic glucose production in the liver. This review describes the unprecedented task of optimizing small molecules in order to affect the appropriate changes in the kinetic parameters of an enzyme. In addition, a pharmacophore model for the various classes of glucokinase activators that have been described in the literature will be presented. Overall, the available data suggests that potent glucokinase activators with the desired effects on the kinetic properties of the enzyme can be designed to achieve strong and persistent antidiabetic effects. GK activators thus represent a promising new treatment for type 2 diabetes.
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Grimsby J., Berthel J. S. and Sarabu R., Glucokinase Activators for the Potential Treatment of Type 2 Diabetes, Current Topics in Medicinal Chemistry 2008; 8 (17) . https://dx.doi.org/10.2174/156802608786413483
DOI https://dx.doi.org/10.2174/156802608786413483 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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