Chapter 3: The Discovery of Piragliatin, a Glucokinase Activator

Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic β-cells and hepatocytes. Glucokinase activators (GKA) represent a novel class of antidiabetic agents that act by increasing the enzymatic activity of GK through its effects on augmenting its maximum velocity and glucose affinity. The discovery and action of the archetypical GKA, RO0281675, has been reported to reduce glucose levels in several rodent models of type 2 diabetes (T2D) mellitus by dual actions on insulin release and suppression of glucose production in the liver. This review describes the medicinal chemistry efforts undertaken to address the formation of an undesirable thiourea metabolite of RO0281675 and research that culminated in the discovery of piragliatin. Piragliatin was found to be devoid of pre-clinical safety concerns, displayed comparable in vivo efficacy in rodent models of type 2 diabetes (T2D) to RO0281675 and was advanced to phase II clinical trials. In a five and a half day multiple ascending dose trial in T2D patients, piragliatin showed rapid, dose-dependent reductions in 24-hour glucose levels resulting from decreases in both fasting and postprandial plasma glucose. In general, piragliatin was safe and well tolerated except for mild to moderate hypoglycemia at the highest doses. Based on the experience gained from piragliatin, Roche is continuing its development of GK activators with subsequent compounds.