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Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR)

Merk, Daniel and Gabler, Matthias and Gomez, Roberto Carrasco and Flesch, Daniel and Hanke, Thomas and Kaiser, Astrid and Lamers, Christina and Werz, Oliver and Schneider, Gisbert and Schubert-Zsilavecz, Manfred. (2014) Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR). Bioorganic & medicinal chemistry, 22 (8). pp. 2447-2460.

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Official URL: https://edoc.unibas.ch/70330/

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Abstract

Nuclear farnesoid X receptor (FXR) has important physiological roles in various metabolic pathways including bile acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toxicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure-activity relationship (SAR) of anthranilic acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative exhibited an EC50 value of 1.5±0.2 μM and 37±2% maximum relative FXR activation. We investigated its SAR regarding polar interactions with the receptor by generating derivatives and computational docking.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Lamers, Christina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0968-0896
e-ISSN:1464-3391
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Nov 2020 10:43
Deposited On:16 Nov 2020 10:43

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