SAR studies on FXR modulators led to the discovery of the first combined FXR antagonistic/TGR5 agonistic compound

Background: Bile acids can serve as signaling molecules by activating the nuclear receptor FXR and the G-protein-coupled receptor TGR5 and both bile acid receptors are prominent experimental drug targets. Results/methodology: In this study we optimized the fatty acid mimetic compound pirinixic acid to a new scaffold with the aim to develop novel FXR modulatory compounds. After a multistep structure-activity optimization process, we discovered FXR agonistic compounds and the first dual FXR antagonistic and TGR5 agonistic compound 79a. Conclusion: With this novel dual activity profile on both bile acid receptors 79a might be a valuable pharmalogical tool to further study the bile acid signaling network.