Optimization of triazole-based TGR5 agonists towards orally available agentsElectronic supplementary information (ESI) available: Detailed experimental procedures for synthesis of compounds 4, 10-18, a dataset of compounds 2-9 used for a plot in Fig. 2, and protocols for cAMP assays, human whole blood assay, and in vivo dog PK studies. See DOI: 10.1039/c2md20174g

Reported herein is a medicinal chemistry effort towards the identification of orally available TGR5 agonist 12 , which served as a dog tool compound for studies to increase confidence in this mechanism. With the challenge of striking the balance of TGR5 potency and desired clearance profile, the screening strategy as well as medicinal chemistry strategy are discussed in this article. With the challenge of striking the balance of TGR5 potency and clearance, the screening strategy as well as medicinal chemistry strategy are discussed in this article.