EXTENDING SAR OF BILE ACIDS AS FXR/TGR5 MODULATORS: SYNTHESIS AND BIOLOGICAL ACTIVITY OF RING C MODIFIED CDCA DERIVATIVES

During the last two decades, there have been extraordinary advances in the knowledge of the chemistry and biology of bile acids (BAs). The astonishing discovery of the hormone-like properties of BAs has led to a complex scenario in which their action was found crucial for a network of signalling pathways, mainly driven by the nuclear receptor Farnesoid X receptor (FXR) and the membrane receptor TGR5, controlling triglyceride, cholesterol, energy and glucose homeostasis. Intense endeavors have thus been dedicated by medicinal chemists to design and develop semisynthetic BA derivatives, natural products and non-steroidal ligands as potent and selective FXR and TGR5 modulators. In particular, the work of our group in the field has elucidated the structure-activity relationships (SAR) of BAs as FXR/TGR5 ligands, identifying functional hot spots on the BA structure and disclosing a number of compounds that are on track for preclinical and clinical assessments of liver and metabolic disorders. These studies have also contributed to show how apparently minor chemical modifications of the BA scaffold influence the physicochemical, pharmacokinetic and pharmacodynamic profiles of the resulting analogues, thereby determining their fate for the advancement in clinical settings. As a continuation of our work in the field, in this communication we report the synthesis and preliminary biological characterization of new BA derivatives as FXR/TGR5 ligands designed with the aim to unveil the role of unexplored positions of the biliary scaffold in the binding and activation of both receptors. Thus, the synthesis of a set of novel BAs bearing diverse structural modifications at ring C, the evaluation of their ability to modulate the FXR and TGR5 receptor, and the results of computational analysis on the hitherto hidden SAR aspects of BAs will be presented and discussed.