Structure‐Based Discovery of Obeticholic Acid Derivatives as Novel Farnesoid X Receptor Partial Agonists with Improved Selectivity and Reduced Off‐Target Effects

The Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that represents an important therapeutic target for gut-liver diseases and metabolic disorders. Recently, FXR partial agonists have gained attention for their potential to minimize side effects resulting from receptor over-activation. In this study, we report the design, synthesis, and biological evaluation of novel obeticholic acid (OCA) derivatives as selective FXR modulators. Structural modifications at the C3α position and the side chain of the bile acid scaffold led to the identification of valine derivatives 2 and 16 as metabolically stable and safe FXR modulators with reduced agonist efficacy. Further molecular dynamics simulations revealed that these compounds induce distinct conformational changes within the FXR ligand-binding domain, consistent with their partial agonist behavior and resulting in moderate modulation of FXR target genes. Unlike OCA, both compounds failed to activate other steroid-responsive receptors, including MRGPRX4 (hX4), a G-protein-coupled receptor implicated in itching in cholestatic patients, supporting their potential as safer FXR modulators with a reduced risk of pruritus-related side effects. Overall, this study elucidates key structure-activity relationships governing FXR partial agonism and hX4 binding and offers valuable chemical tools for the development of FXR-targeted therapeutics with improved safety profiles.