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SAR studies on FXR modulators led to the discovery of the first combined FXR antagonistic/TGR5 agonistic compound
Journal
Future medicinal chemistry
Volume
8
Number
2
Pages / Article-Number
133-48
Mesh terms
Benzoic Acid, chemistry, pharmacology; Bile Acids and Salts, chemistry, pharmacology; Cell Line, Tumor; HeLa Cells; Humans; Protein Binding; Receptors, Cytoplasmic and Nuclear, antagonists & inhibitors, metabolism; Receptors, G-Protein-Coupled, agonists, metabolism; Structure-Activity Relationship; Transcriptional Activation, drug effects
Abstract
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.; 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.
