Development of bile acid activated receptors hybrid molecules for the treatment of inflammatory and metabolic disorders.

The farnesoid-x-receptor (FXR) and the G protein bile acid activated receptor (GPBAR)1 are two bile acid activated receptors highly expressed in entero-hepatic, immune, adipose and cardiovascular tissues. FXR and GPBAR1 are clinically validated targets in the treatment of metabolic disorders and FXR agonists are currently trialled in patients with non-alcoholic steato-hepatitis (NASH). Results of these trials, however, have raised concerns over safety and efficacy of selective FXR ligands suggesting that the development of novel agent designed to impact on multiple targets might have utility in the treatment of complex, multigenic, disorders. Harnessing on FXR and GPBAR1 agonists, several novel hybrid molecules have been developed, including dual FXR and GPBAR1 agonists and antagonists, while exploiting the flexibility of FXR agonists toward other nuclear receptors, dual FXR and peroxisome proliferators-activated receptors (PPARs) and liver-X-receptors (LXRs) and Pregnane-X-receptor (PXR) agonists have been reported. In addition, modifications of FXR agonists has led to the discovery of dual FXR agonists and fatty acid binding protein (FABP)1 and Leukotriene B4 hydrolase (LTB4H) inhibitors. The GPBAR1 binding site has also proven flexible to accommodate hybrid molecules functioning as GPBAR1 agonist and cysteinyl leukotriene receptor (CYSLTR)1 antagonists, as well as dual GPBAR1 agonists and retinoid-related orphan receptor (ROR)γt antagonists, dual GPBAR1 agonist and LXR antagonists and dual GPBAR1 agonists endowed with inhibitory activity on dipeptidyl peptidase 4 (DPP4). In this review we have revised the current landscape of FXR and GPBAR1 based hybrid agents focusing on their utility in the treatment of metabolic associated liver disorders.