Background: Glucokinase (GK), a cytoplasmic enzyme catalyzes the metabolism of glucose to glucose-
6-phosphate with the help of ATP and aids in the controlling of blood glucose levels within the normal range
in humans. In pancreatic β-cells, it plays a chief role by controlling the glucose-stimulated secretion of insulin and
in liver hepatocyte cells, it controls the metabolism of carbohydrates. GK acts as a promising drug target for the
pharmacological treatment of patients with type 2 diabetes mellitus (T2DM) as it plays an important role in the
control of carbohydrate metabolism.
Methods: Data used for this review was based on the search from several science databases as well as various
patent databases. The main data search terms used were allosteric GK activators, diabetes mellitus, type 2 diabetes,
glucokinase, glucokinase activators and human glucokinase.
Results: This article discusses an overview of T2DM, the biology of GK, the role of GK in T2DM, recent updates
in the development of small molecule GK activators reported in recent literature, mechanism of action of GK
activators and their clinical status.
Conclusion: GK activators are the novel class of pharmacological agents that enhance the catalytic activity of GK
enzyme and display their antihyperglycemic effects. Broad diversity of chemical entities including benzamide
analogues, carboxamides, acrylamides, benzimidazoles, quinazolines, thiazoles, pyrimidines, pyridines, orotic
acid amides, amino acid derivatives, amino phosphates and urea derivatives have been synthesized in past two
decades as potent allosteric activators of GK. Presently, the pharmaceutical companies and researchers are focusing
on the design and development of liver-selective GK activators for preventing the possible adverse effects
associated with GK activators for the long-term treatment of T2DM.