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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.

A new sulfated sterol, phallusiasterol C (1), has been isolated from the Mediterranean ascidian Phallusia fumigata and its structure has been determined on the basis of extensive spectroscopic (mainly 2D NMR) analysis. The possible role in regulating the pregnane X receptor (PXR) activity of phallusiasterol C has been investigated; although the new sterol resulted inactive, this study adds more items to the knowledge of the structure-PXR regulating activity relationships in the case of sulfated steroids.

Bile acids are the endogenous modulators of the nuclear receptor FXR and the membrane receptor GPBAR1. FXR represents a promising pharmacological target for the treatment of cholestatic liver disorders. Currently available semisynthetic bile acid derivatives cover the same chemical space of bile acids and therefore they are poorly selective toward BA receptors, increasing patient risk for adverse side effects. In this report, we have investigated around the structure of CDCA describing the synthesis and the in vitro and in vivo pharmacological characterization of a novel family of compounds modified on the steroidal tetracyclic core and on the side chain. Pharmacological characterization resulted in the identification of several potent and selective FXR agonists. These novel agents might add utility in the treatment of cholestatic disorders by potentially mitigating side effects linked to unwanted activation of GPBAR1.

Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1.

Bile acids, the end-products of cholesterol catabolism, are signaling molecules activating several cellular networks through the recognition of nuclear and membrane receptors, such as the farnesoid-x-receptor (FXR) and a G-proteins coupled receptor (GP-BAR1). BAs are generated in the liver as primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), conjugated with glycine and taurine, and then secreted in the small intestine and transformed by the intestinal microbiota into secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). CDCA is the endogenous agonist of FXR while LCA and its corresponding tauro- and glyco-conjugates (GLCA and TLCA) are the most potent natural agonists for GP-BAR1. The main physiological role of FXR is the regulation of bile acids absorption, synthesis and secretion in the intestine, liver and kidney and it is considered a promising target in cholestasis. Although, GP-BAR1 agonists represent a novel opportunity in the treatment of entero-hepatic and metabolic disorders, a recent study has provided evidence that this receptor is the physiologic mediator of pruritus, a common symptom observed in cholestasis. In this contest, we have manipulated the bile acids scaffolds to obtain a potential lead compound in the treatment of entero-hepatic and metabolic disorders. [