MB06322 (CS-917): A Potent and Selective Inhibitor of Fructose 1,6-Bisphosphatase for Controlling Gluconeogenesis in Type 2 Diabetes

In type 2 diabetes, the liver produces excessive amounts of glucose through the gluconeogenesis (GNG) pathway and consequently is partly responsible for the elevated glucose levels characteristic of the disease. In an effort to find safe and efficacious GNG inhibitors, we targeted the AMP binding si...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-05, Vol.102 (22), p.7970-7975
Main Authors: Erion, Mark D., van Poelje, Paul D., Dang, Qun, Kasibhatla, Srinivas Rao, Potter, Scott C., Reddy, M. Rami, Reddy, K. Raja, Jiang, Tao, Lipscomb, William N.
Format: Article
Language:English
Subjects:
Adenosine Monophosphate - metabolism
Alanine - analogs & derivatives
Alanine - pharmacology
Alanine - therapeutic use
Analysis of Variance
Animals
Binding sites
Biological Sciences
Carbon Radioisotopes - metabolism
Diabetes
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Dose-Response Relationship, Drug
Drug Design
Enzymes
Fructose-Bisphosphatase - antagonists & inhibitors
Fructose-Bisphosphatase - metabolism
Gluconeogenesis - drug effects
Glucose
Hepatocytes
Humans
Lactates
Liver
Liver - metabolism
Male
Molecular Mimicry
Organophosphonates - pharmacology
Organophosphonates - therapeutic use
Organophosphorus Compounds - pharmacology
Organophosphorus Compounds - therapeutic use
Phosphates
Phosphonic acids
Prodrugs
Rats
Rats, Sprague-Dawley
Rats, Zucker
Spectrophotometry
Thiazoles - pharmacology
Thiazoles - therapeutic use
Type 2 diabetes mellitus
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Summary:In type 2 diabetes, the liver produces excessive amounts of glucose through the gluconeogenesis (GNG) pathway and consequently is partly responsible for the elevated glucose levels characteristic of the disease. In an effort to find safe and efficacious GNG inhibitors, we targeted the AMP binding site of fructose 1,6-bisphosphatase (FBPase). The hydrophilic nature of AMP binding sites and their widespread use for allosteric regulation of enzymes in metabolic pathways has historically made discovery of AMP mimetics suitable for drug development difficult. By using a structure-based drug design strategy, we discovered a series of compounds that mimic AMP but bear little structural resemblance. The lead compound, MB05032, exhibited high potency and specificity for human FBPase. Oral delivery of MB05032 was achieved by using the bisamidate prodrug MB06322 (CS-917), which is converted to MB05032 in two steps through the action of an esterase and a phosphoramidase. MB06322 inhibited glucose production from a variety of GNG substrates in rat hepatocytes and from bicarbonate in male Zucker diabetic fatty rats. Analysis of liver GNG pathway intermediates confirmed FBPase as the site of action. Oral administration of MB06322 to Zucker diabetic fatty rats led to a dose-dependent decrease in plasma glucose levels independent of insulin levels and nutritional status. Glucose lowering occurred without signs of hypoglycemia or significant elevations in plasma lactate or triglyceride levels. The findings suggest that potent and specific FBPase inhibitors represent a drug class with potential to treat type 2 diabetes through inhibition of GNG.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0502983102