Glucokinase activators as new type 2 diabetes therapeutic agents

Background: Small molecule glucokinase activators (GKAs) represent a new strategy to treat type 2 diabetes. Glucokinase (GK) primarily exerts its effect through modulatory actions in the pancreatic β-cells and the liver. It couples insulin secretion in the pancreas with plasma glucose concentration, and improves glucose utilization in the liver, thus affecting two key aspects of glucose homeostasis. Objective and method: To review currently disclosed GKA structures and to classify them based on the key structural features. For this purpose, the data from patent disclosures and publications are used. Also, published in vitro findings on related lead GKAs are used to compare their effect on GK kinetics. Results and conclusion: The most common GKA pharmacophore consists of a center, which can be a carbon or an aromatic ring, and three attachments. Two of these are hydrophobic groups, with at least one of them being an aromatic ring. The third attachment, without exception, consists of an H-bond donor-acceptor pair in the form of a heterocyclic amine, or an N-acyl urea. These structurally diverse GKAs show important differences in their effects on the kinetic properties of GK.