Discovery of amine bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1

Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors, providing new opportunities for the treatment of enterohepatic and metabolic disorders. Because endogenous bile acids often target both receptor families, the development of selective ligands on steroidal scaffold has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. To design selective agonists it is essential to know the BAs structural requisites to interact with GPBAR1 and FXR. A full understanding of the effects of BAs modifications on the activity and selectivity towards GPBAR1 and FXR is possible only revealing the binding modes of these compounds to the two receptors, on the basis of our knowledge on GP-BAR1 structure. Therefore, we have modified the scaffold of LCA by replacing the BA 3α-OH with an -NH2 group and developed a small library of amine LCA derivatives. The compounds have been synthesized and tested on FXR and GPBAR1 through specific pharmacological assays. Our rational drug design allowed identifying the first amine LCA derivatives as selective GPBAR1 agonists elucidating also their binding mode to the receptor. All the gathered information is valuable to design more potent and drug-like GP-BAR1 selective ligands.