Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH

Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5. In this letter, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic properties, but also proved superior pharmacological efficacy in the HFD + CCl4 model.