Inspection on bile acid scaffold in the discovery of the first example of LXR/GPBAR1 dual agonists

Hyodeoxycholic acid (HDCA), also known as 3α,6α-dihydroxy-5β-cholan-24-oic acid, is a secondary hydrophilic bile acid formed in human small intestine by bacterial C-6 hydroxylation of lithocholic acid. BAs are signaling molecules that activate at least four members of the nuclear receptors (NRs) superfamily: the farnesoid X receptor (FXR, NR1H4), identified as the endogenous bile acid sensor, the constitutive androstane receptor (CAR, NR1I3), the pregnane X receptor (PXR, NR1I2), the liver X receptor and the vitamin D receptor (VDR, NR1I1). In addition, secondary BAs activate G protein-coupled receptors (GPCRs), including GPBAR1 (also known as M-BAR, TGR5 or BG37). Several studies affirmed the therapeutical potential of HDCA administration in various metabolic disorders. HDCA has been shown to prevent gallstone formation, to reduce the levels of cholesterol in the liver and in the plasma suggesting its beneficial effects in the treatment of increased plasma cholesterol levels and atherosclerosis. In this communication, we report a novel library of semisynthetic bile acid derivatives obtained by modifications on the HDCA scaffold. The pharmacological characterization of this library led to the discovery of the first examples of novel dual ligands for LXR and GP-BAR1 receptors that might hold utility in the treatment of several metabolic disorders such as obesity and atherosclerosis