Type 2 diabetes affects over 9 per cent of the US population and is characterised by either low levels of, or an inadequate response to insulin - a hormone secreted by the pancreas to release energy from the breakdown of carbohydrates.
The January 16th issue of the Proceedings of the National Academies of Science (PNAS), contains two articles focusing on non-peptidic small molecule agonists for the glucagon-like peptide-1 (GLP-1). Both of the articles demonstrate the feasibility of synthesising non-peptidic GLP-1 agonists, which are suitable for oral administration.
GLP-1 is a gastrointestinal hormone, or incretin, that stimulates insulin secretion by the pancreas and suppresses the release of glucagons as well as slowing digestion and absorption and moderating blood glucose levels, making it an ideal candidate as a diabetes therapy.
Unfortunately, the peptide only has a half-life of 5 minutes in the vascular system due to destruction by dipeptidyl peptidase-IV (DPP-IV) and rapid renal clearance and degradation. This means that frequent, high dose administrations would be needed for GLP1 to be effective.
A plethora of research has looked at inhibiting the mechanism of DPP-IV and many drug candidates are currently in clinical trials. Merck's DPP-IV inhibitor Januvia (sitagliptin), was approved in the US for type two diabetes in October 2006.
Two incretin mimics that are resistant to DPP-IV are in the pipeline: Amylin and Eli Lilly's Byetta (exenatide) which has been approved in the EU and US and is now on the market, and Novo Nordisk's liraglutide (NN2211), which entered Phase III trials in February 2006. However, the need for the injection of these peptides limits the attractiveness of these treatments.
Researchers from Novo Nordisk, Pfizer and the University of Copenhagen screened 500,000 small molecules in an attempt to find a specific GLP-1 agonist by competitive binding experiments. However, using a functional assay they discovered that substituted quinoxalines specifically activated the GLP-1 receptor.
By systematically varying the substituents they discovered a molecule that significantly increases glucose stimulated insulin release from wild-type mouse islets, but not from GLP-1 receptor knockout mouse islets.
The compound was not particularly potent but may prove a useful starting point for further studies.
Researchers from Shanghai discovered an orthosteric GLP-1 agonist that they named Boc5. They initially started out by screening 50,000 compounds, which after further investigation revealed that substituted cyclobutanes could act as orthosteric GLP-1 agonists.
The molecule was found to amplify glucose-stimulated insulin secretion in rat pancreatic islets. Chronic in vivo administration of Boc5 in mice normalised blood glucose levels and reduced body weight gain, as well as having greater glucose tolerance and lower insulin levels. In fact, up to 20 per cent weight loss was observed, leading the authors to postulate that the drug could also be used as an antiobesity therapy.
Crucially, Boc5 appears to be orally active, acutely reducing mice food intake after oral administration. The authors noted that the antidiabetic effects of Boc5 appear to extend beyond the treatment period, which they suggest may imply an effect of beta-cell neogenesis and differentiation.
The authors state that an optimised drug is likely to require greater potency, but that the findings have the potential to spawn a new class of orally available GLP-1 agonists for the treatment of metabolic diseases.