Discovery, Structure-Activity Relationships, and in Vivo Activity of Dihydropyridone Agonists of the Bile Acid Receptor TGR5.
JOURNAL OF MEDICINAL CHEMISTRY（2023）
Univ Lille | Univ Artois
Abstract
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.
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Bile Acids
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