Avicholic Acid: A Primary Bile Acid from Birds on the Route to Potent and Selective TGR5 Ligands

Bile acid (BA) activated receptors are widely recognized as relevant targets for drug discovery efforts. The key members of this family, namely FXR and TGR5, are implicated in a number of liver and metabolic diseases such as cholestasis, non-alcoholic steatohepatitis (NASH), obesity and type II diabetes.[1] In this framework, we have developed a small library of BA derivatives which was instrumental to defined the SAR of BAs as FXR/TGR5 agonists and to disclose selective and potent ligands for both receptors (Figure 1).[2] As a continuation of our efforts aimed at finding novel potent and selective chemical tools to probe the functions of BA related receptors in different tissues, we have been engaged in the further chemical elaborations of the BA scaffold. Our attention, in particular, was attracted by the peculiar structure of avicholic acid, a natural BA isolated from avian species (Shoebill stork and herons) and characterized by a hydroxy group at the C16-position (Figure 1). Polar groups at this position were indeed suggested by our QSAR model as favoring the activity to the TGR5 receptor.[3] Starting from this observation, we report the synthesis, the biological and PK appraisals, and structure activity relationships of novel avicholic acid derivatives as TGR5 ligands.