In the last years, bile acid receptors FXR and GPBAR1 have emerged as prominent targets for treatment of several human diseases, ranging from liver cholestatic disorders to metabolic syndrome, nonalcoholic steatohepatitis (NASH) and diabetes.
Even if dual FXR/GPBAR1 agonists are considered a novel opportunity in the treatment of these diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation associates with severe side effects.
Since bile acids often target both receptor families, speculation on non-steroidal ligands, although still in its infancy, represents a promising strategy to selectively target GPBAR1. Indeed, selective GPBAR1 modulators allow controlling glucose metabolism through the release of glucagon-like peptide (GLP)-1 without affecting the FXR-related pathways.
The availability of the tridimensional model of the above receptors has opened new avenues for the rational design of selective modulators. Using such structural information, we are currently involved in developing novel active ligands with improved drug-like properties and a rational modulation of BA receptors activity.
These studies have allowed identifying the first example of non-steroidal GPBAR1 antagonist, which might open the way to a new and promising field of research representing a tool in dissecting and in shedding light on the complex biological pathways under GPBAR1 control
