Novel small-molecules stimulating GLP-1 secretion: innovative treatment for diabesity and liver diseases.
Prof. Mauro Pineschi, University of Pisa; Dr Francesco Berti, Italian Institute of Technology; Dr Andrea Menichetti, University of Pisa
University of Pisa
The challenge is to find low cost, orally available new treatments for diabetes and obesity (diabesity), liver diseases and related pathologies by means of novel mechanisms of action.
The inventors have found by serendipity a novel molecular architecture that is able to enhance the secretion of GLP-1 both in vitro and in vivo. The chemistry developed is completely original and robust. GLP-1 is a gastrointestinal peptide hormone that potentiates glucose-stimulated secretion of insulin, decreases gastric emptying, and suppress food intake. A beneficial effect on liver diseases (fatty liver, NASH) and on neurodegenerative diseases (Alzheimer, Parkinson) by activation of GLP-1 secretion has also been recently demonstrated. The new stable compounds having GLP-1 secretagogue activity can be conveniently exploited for the introduction in therapy of new orally active drugs for the treatment of type 2 diabetes, obesity, non-alcoholic fat leaver disease (NAFLD) and neurodegenerative diseases (AD, PD). The novelty, inventive steps and industrial applicability of our discovery have been officially recognized by the international search report of our PCT. The in vitro experimental data and in silico ADME and toxicity prediction are completely drug-like and encouraging. In vivo experiments in db/db mice are also particularly promising with a prominent increase of insulin secretion.
Our invention has a possible industrial application consisting in the development of an orally active drug, which can afford benefits in the cure management of type 2 diabetes with an improved patient compliance and reduced therapeutic costs. Nowadays, structural analogs of GLP-1 are commercially available (as for example liraglutide, semaglutide, exenatide etc.) to treat decompensated diabetes. But since these molecules are peptides, they can only be delivered by injection and have limited stability and very high cost. When dealing with potential new drug treatments the time-to-market is very hard to foresee. Anyway, as pathologies connected with diabesity (diabetes + obesity) and neurodegenerative diseases (AD, PD) in the western society are widespread the commercial opportunities are sound and manifold. Thus, potentially, the activation of GLP-1 secretion by small molecules is a very lucrative field. The technology is available for in-licensing and for further co-development.
In vivo experiments in db/db mice showed a significant increase of GLP-1 and insulin secretions. We are currently providing chemical modifications of the original scaffold in order to find molecules active in the low nanomolar range for GLP-1 secretion. At the same time, still with academic research partners, we have very promising data for their neuroprotective activity on human astrocytes. We are willing to find investors in order to carry out a complete pre-clinical package before entering clinical trials.
Granted USA and Italian Patent. European patent application has been filed.
- Alhadeff R., Warshel A. Proteins. (2020); 88:127-134 Epub 2019 Aug 2;
- Seghieri, M., Christensen, A. S., Andersen, A., Solini, A., Knop, F. K., & Vilsbøll, T. Frontiers in endocrinology (2018) 9: 649. 2
- Yun, S. P. et al. Nature Medicine (2018) 24, 932.