Abstract
Glucose-phosphorylating enzyme, glucokinase (GK) plays a major role in glucose homeostasis primarily through its regulatory actions in pancreatic β-cells and liver hepatocytes. Conversion of glucose to glucose-6-phosphate by GK promotes glycogen synthesis in liver hepatocytes, and insulin release in the pancreatic β-cells. Small molecules called glucokinase activators (GKAs) which bind to an allosteric activator site of the GK enzyme have indeed been discovered and developed, and thus hold great promise as new, effective and safe antidiabetic agents. GKAs enhance the catalytic activity of GK and promising clinical trials in humans demonstrated that they are highly useful in the treatment of type 2 diabetes mellitus. Most of the reported GKAs include amide derivatives like benzamides, acrylamides, carboxamides, acetamides and acrylamides. Examples include Piragliatin, AZD1656, AZD6370, R1440 GKA2, GKA 50, YH GKA, PSN 010, and LY2121260. Recent findings on GKAs including lead compounds and overview of current hypothesis on mechanism of GK activation along with summary of the recently published patents as well as the GKAs of natural origin are reported in the present review.
Keywords: Benzamides, Diabetes mellitus, Glucokinase, Glucokinase activators, T2DM.
Mini-Reviews in Medicinal Chemistry
Title:Recent Updates on Glucokinase Activators for the Treatment of Type 2 Diabetes Mellitus
Volume: 14 Issue: 7
Author(s): Ajmer Singh Grewal, Bhupinder Singh Sekhon and Viney Lather
Affiliation:
Keywords: Benzamides, Diabetes mellitus, Glucokinase, Glucokinase activators, T2DM.
Abstract: Glucose-phosphorylating enzyme, glucokinase (GK) plays a major role in glucose homeostasis primarily through its regulatory actions in pancreatic β-cells and liver hepatocytes. Conversion of glucose to glucose-6-phosphate by GK promotes glycogen synthesis in liver hepatocytes, and insulin release in the pancreatic β-cells. Small molecules called glucokinase activators (GKAs) which bind to an allosteric activator site of the GK enzyme have indeed been discovered and developed, and thus hold great promise as new, effective and safe antidiabetic agents. GKAs enhance the catalytic activity of GK and promising clinical trials in humans demonstrated that they are highly useful in the treatment of type 2 diabetes mellitus. Most of the reported GKAs include amide derivatives like benzamides, acrylamides, carboxamides, acetamides and acrylamides. Examples include Piragliatin, AZD1656, AZD6370, R1440 GKA2, GKA 50, YH GKA, PSN 010, and LY2121260. Recent findings on GKAs including lead compounds and overview of current hypothesis on mechanism of GK activation along with summary of the recently published patents as well as the GKAs of natural origin are reported in the present review.
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Grewal Singh Ajmer, Sekhon Singh Bhupinder and Lather Viney, Recent Updates on Glucokinase Activators for the Treatment of Type 2 Diabetes Mellitus, Mini-Reviews in Medicinal Chemistry 2014; 14 (7) . https://dx.doi.org/10.2174/1389557514666140722082713
DOI https://dx.doi.org/10.2174/1389557514666140722082713 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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