Discovery, Structure–Activity Relationships, and In Vivo Activity of Dihydropyridone Agonists of the Bile Acid Receptor TGR5

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.