Structure‐Based Discovery of Obeticholic Acid Derivatives as Novel Farnesoid X Receptor Partial Agonists with Improved Selectivity and Reduced Off‐Target Effects
Daniela Passeri, Bruno Cerra, Andrea Carotti, Francesco Greco, Sara Piermarini, Carolina Colliva, Paride Liscio, Francesca De Franco, Luciano Adorini, Mary Ruth Erickson, Roberto Pellicciari, Antimo Gioiello
TL;DR
Scientists designed new versions of a drug that target a liver receptor more safely, reducing side effects like itching.
Contribution
The study introduces novel obeticholic acid derivatives with improved FXR selectivity and reduced off-target activation.
Findings
Valine derivatives 2 and 16 are metabolically stable FXR modulators with reduced agonist efficacy.
The compounds do not activate MRGPRX4, reducing the risk of pruritus-related side effects.
Structure–activity relationships for FXR partial agonism and hX4 binding were elucidated.
Abstract
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…
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Taxonomy
TopicsDrug Transport and Resistance Mechanisms · Cholesterol and Lipid Metabolism · Diabetes Treatment and Management