Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for “Diabesity”
“Diabesity” refers to diabetes occurring in the context of obesity, which is a fast-growing epidemic worldwide. The lack of innovative therapies capable of preventing or effectively treating this syndrome is resulting in severe impairment in the quality of life of many people.
The discovery of glucagon-like peptide (GLP) and the development of therapeutic strategies to favor its physiological action are enabling new avenues toward such an unmet clinical need. Significant interest exists in the development of drugs able to target a GLP-1R allosteric site for enhanced receptor specificity, while displaying good bioavailability (particularly oral absorption).
In this work, a Vivia Biotech chemical library of approximately 2500 compounds was screened on the ExviTech platform (conc. of 10 µM). A starting hit compound (oxadiazole 1) was identified as a putative modulator of the GLP-1 receptor. A series of derivatives containing different piperidine substituents were subsequently prepared by GalChimia, leading to the discovery of small molecule V-0219, a very potent positive allosteric modulator (PAM) of GLP-1R able to double insulin secretion at nanomolar concentrations.
The compound showed remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. The hERG and selectivity profiles were also suitable for further development. Moreover, since V-0219 contains a stereocenter, the evaluation of the activity of each enantiomer became a priority and enantioselective synthesis was also carried out. Notably, the synthesized (S)-enantiomer was found to show oral efficacy in animal models. Overall, the characteristics of this compound are valuable as an orally active PAM of GLP-1R.
You can read the full paper here: J. Med. Chem. 2022. DOI: 10.1021/acs.jmedchem.1c01842. (Open Access)
The present work was developed within the collaborative project HUMANFARMA: Translational Drug Discovery Directly in Patient Samples, led by Vivia Biotech and financed by the Ministry of Economy and Competitiveness through FEDER.