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.