SAR studies on FXR modulators led to the discovery of the first combined FXR antagonistic/TGR5 agonistic compound. (February 2016)

• Record Type: Journal Article
• Authors: Lamers, Christina; Merk, Daniel; Gabler, Matthias; Flesch, Daniel; Kaiser, Astrid; Schubert-Zsilavecz, Manfred
• Is Part Of: Future medicinal chemistry. Volume 8:Number 2(2016)
• Page Start: 133
• Page End: 148
• Publication Date: 2016-02
• Subjects: bile acid signaling -- bile acid receptor modulator -- farnesoid X receptor -- FXR antagonist -- metabolic disorders -- non-alcoholic steatohepatitis; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc.15.178
• Languages: English
• ISSNs: 1756-8919

Abstract

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 compound79a .Conclusion: With this novel dual activity profile on both bile acid receptors79a might be a valuable pharmalogical tool to further study the bile acid signaling network.