Chemical exploration of TGR5 functional hot-spots: Synthesis and structure-activity relationships of C7- and C23-Substituted cholic acid derivatives.

The activation of TGR5 bestows on bile acids the ability to modulate nongenomic signaling pathways, which are responsible of physiological actions including immunosuppressive and anti-inflammatory properties as well as the regulation of glucose metabolism and energy homeostasis. TGR5 agonists have therefore emerged in drug discovery and preclinical appraisals as promising compounds for the treatment of liver diseases and metabolic syndrome. In this study, we have been devising site-selected chemical modifications of the bile acid scaffold to provide novel chemical tools able to modulate the functions of TGR5 in different tissues. Biological results of the tested collection of semisynthetic cholic acid derivatives were used to extend the structure-activity relationships of TGR5 agonists and to clarify the molecular basis and functional role of TGR5 hot-spots in the receptor activation and selectivity. Some unexpected properties deriving from the molecular structure of bile acids have been unveiled as relevant to the receptor activation and may hence be used to design novel, selective and potent TGR5 agonists. [Display omitted] • The synthesis of a collection of novel semisynthetic cholic acid derivatives is reported. • The C 7 β-butyl-CA (8) and the C 23 -difluoro-CA (19) were identified as selective low micromolar TGR5 agonists. • Biological data and computational modelling evidenced for the first time the negative impact of the 6α-ethyl group in the TGR5 activity of bile acids. • Unprecedented insights into the functional role of TGR5 hot-spots are reported and may be explored to design potent and selective TGR5 agonists. [ABSTRACT FROM AUTHOR]