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

    Christina Lamers

    *Author for correspondence:

    E-mail Address: lamers@pharmchem.uni-frankfurt.de

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany

    ,
    Daniel Merk

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany

    ,
    Matthias Gabler

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany

    ,
    Daniel Flesch

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany

    ,
    Astrid Kaiser

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany

    &
    Manfred Schubert-Zsilavecz

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany

    Published Online:https://doi.org/10.4155/fmc.15.178

    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 compound 79a. Conclusion: 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.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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