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

Future Medicinal Chemistry
Christina LamersManfred Schubert-Zsilavecz

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.

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Citations

Oct 19, 2016·Journal of Digestive Diseases·Zhi Qing Yuan, Ke Wei Li
Dec 15, 2017·Journal of Biomolecular Structure & Dynamics·Thales KronenbergerVinicius G Maltarollo
Jul 4, 2019·Nature Communications·Daniel MerkHarald Schwalbe
May 3, 2018·Scientific Reports·Matthias GablerDaniel Merk

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Methods Mentioned

BETA
thermal shift
transfection

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