Discovery of a Novel Class of Dual GPBAR1 Agonists-RORγt Inverse Agonists for the Treatment of IL-17-Mediated Disorders

Retinoic acid receptor-related orphan receptor gamma-t (ROR gamma t) and GPBAR1, a transmembrane G-protein-coupled receptor for bile acids, are attractive drug targets to develop clinically relevant small modulators as potent therapeutics for autoimmune diseases. Herein, we designed, synthesized, and evaluated several new bile acid-derived ligands with potent dual activity. Furthermore, we performed molecular docking and MD calculations of the best dual modulators in the two targets to identify the binding modes as well as to better understand the molecular basis of the inverse agonism of ROR gamma t by bile acid derivatives. Among these compounds, 7 was identified as a GPBAR1 agonist (EC50 5.9 mu M) and ROR gamma t inverse agonist (IC(5)0 0.107 mu M), with excellent pharmacokinetic properties. Finally, the most promising ligand displayed robust anti-inflammatory activity in vitro and in vivo in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.

Automated summary

Researchers designed and synthesized bile acid-derived ligands with potent dual activity, and compound 7 showed excellent pharmacokinetic properties and robust anti-inflammatory activity.