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Discovery, Structure–Activity Relationships, and In Vivo Activity of Dihydropyridone Agonists of the Bile Acid Receptor TGR5
- Source :
- Journal of Medicinal Chemistry; September 2023, Vol. 66 Issue: 17 p11732-11760, 29p
- Publication Year :
- 2023
-
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.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Volume :
- 66
- Issue :
- 17
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs63816019
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c01881