Lead optimization of the bile acid scaffold led to INT-747 (4), an approved drug for the treatment of primary biliary cholangitis and dual agonist of GPBAR1 and FXR as well as INT-777 (2), a more selective GPBAR1 agonist (Pellicciari et al., 2009; Fiorucci et al., 2014; Floreani and Mangini, 2018). This evidence concerns the gene GPBAR1 and primary biliary cholangitis.