Sylvain Picon, Rajaa Boulahjar, Vanessa Hoguet, Morgane Baron, Isabelle Duplan, Emmanuelle Vallez, Nathalie Hennuyer, Julie Dumont, Véronique Touche, Emilie Dorchies, Manuel Lasalle, Amandine Descat, Catherine Piveteau, Alexandre Biela, Ludovic Chaput, Bruno O Villoutreix, Emmanuelle Lipka, Emmanuel Sevin, Maxime Culot, Fabien Gosselet, Sophie Lestavel, Pascal Roussel, Rebecca Deprez-Poulain, Florence Leroux, Bart Staels, Benoit Deprez, Anne Tailleux, Julie Charton
A novel series of potent agonists of the bile acid receptor TGR5 bearing a dihydropyridone scaffold was developed from a high-throughput screen. Starting from a micromolar hit compound, we implemented an extensive structure-activity-relationship (SAR) study with the synthesis and biological evaluation of 83 analogues. The project culminated with the identification of the potent nanomolar TGR5 agonist 77A . We report the GLP-1 secretagogue effect of our lead compound ex vivo in mouse colonoids and in vivo. In addition, to identify specific features favorable for TGR5 activation, we generated and optimized a three-dimensional quantitative SAR model that contributed to our understanding of our activity profile and could guide further development of this dihydropyridone series...
August 28, 2023: Journal of Medicinal Chemistry