Anti-diabetics to activate endogenous hormone release
Type 2 diabetes (T2D) incidence is increasing globally at an unprecedented pace. Although a range of treatments are available for the management of the symptoms, long term administration can cause side-effects. In T2D patients, the ability of L-cells in the mucosa of the digestive tract (jejunum to colon) to produce Glucagon-like peptide-1 (GLP-1) is reduced. GLP-1 has been identified as a key signalling hormone in diabetes, with GPR-119 receptors mediating GLP-1 release.
Research at Curtin University has shown a dietary phospholipid, oleoyl-lysophosphatidylinositol (O-LPI) which is found at low concentrations in some types of food, strongly induces the release of GLP-1 from L-cells, with high potency by activating GPR-119. A new class of synthetic analogues of O-LPI has been shown to have powerful GLP-1 secreting activity and improved stability. These molecules act directly on L-cells in the digestive tract, harnessing the natural mechanism of release of GLP-1 and are expected to have very low toxicity and few side effects.
These new chemical entities (NCEs) are easy to synthesise, have been designed to be protected from degradation in the stomach, and can be administered as medicine, or as a functional additive to food. They represent an exciting new approach to the management of T2D.
These NCEs are:
- nontoxic and harness endogenous GLP-1 release
- direct acting on cells in the intestine
- resistant to degradation in the digestive tract
- easy to synthesise and cost effective for production at scale
- suitable for pharmaceutical or functional food applications.
Professor Marco Falasca (School of Biomedical Sciences) is collaborating with synthetic chemists Associate Professor Max Massi and Dr Peter Simpson (School of Molecular & Life Sciences) at Curtin University. The team have extensive expertise in medicinal chemistry, structure-activity relationships, diagnostics and drug development.
Stage of development
A series of compounds from the novel class of compounds have been synthesized and the structure-activity relationship (SAR) was defined in GLP-1 release assay using in vitro (mouse GLUTag and human NCI-H717 cells) and ex vivo models of GLP-1 release.
O-LPI has a high efficacy in inducing GLP-1 secretion in human NCI-H716 cells at 20 µM concentration, in the presence of 10 mM glucose (>200% relative to oleoyl-ethanolamide; OEA). A lead compound, PS-316a, has an EC50 of 22.35 µM for GLP-1 release in NCI-H716 cells.
Example compounds have shown no toxicity at the highest concentrations tested (100 μM) using a highly sensitive Zebrafish model.
Testing in the db/db mice model of diabetes is planned with preliminary results expected to be available mid-2018.
An Australian provisional patent was filed on 1 September 2017.
Curtin is seeking development partners to collaborate in the development of new diabetes treatments by completing preclinical testing and take a lead compound into clinical human studies under license.
Russell Nicholls – Deputy Director, Commercialisation, Curtin University
Phone: +61 410 285554