Fructose-1, 6-bisphosphatase inhibitors for reducing excessive endogenous glucose production in type 2 diabetes

Abstract

Fructose-1,6-bisphosphatase (FBPase), a rate-controlling enzyme of gluconeogenesis, has emerged as an important target for the treatment of type 2 diabetes due to the well-recognized role of excessive endogenous glucose production (EGP) in the hyperglycemia characteristic of the disease. Inhibitors of FBPase are expected to fulfill an unmet medical need because the majority of current antidiabetic medications act primarily on insulin resistance or insulin insufficiency and do not reduce gluconeogenesis effectively or in a direct manner. Despite significant challenges, potent and selective inhibitors of FBPase targeting the allosteric site of the enzyme were identified by means of a structure-guided design strategy that used the natural inhibitor, adenosine monophosphate (AMP), as the starting point. Oral delivery of these anionic FBPase inhibitors was enabled by a novel diamide prodrug class. Treatment of diabetic rodents with CS-917, the best characterized of these prodrugs, resulted in a reduced rate of gluconeogenesis and EGP. Of note, inhibition of gluconeogenesis by CS-917 led to the amelioration of both fasting and postprandial hyperglycemia without weight gain, incidence of hypoglycemia, or major perturbation of lactate or lipid homeostasis. Furthermore, the combination of CS-917 with representatives of the insulin sensitizer or insulin secretagogue drug classes provided enhanced glycemic control. Subsequent clinical evaluations of CS-917 revealed a favorable safety profile as well as clinically meaningful reductions in fasting glucose levels in patients with T2DM. Future trials of MB07803, a second generation FBPase inhibitor with improved pharmacokinetics, will address whether this novel class of antidiabetic agents can provide safe and long-term glycemic control. © 2011 Springer-Verlag.