Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR).
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4501203
Author(s) Merk, Daniel; Gabler, Matthias; Gomez, Roberto Carrasco; Flesch, Daniel; Hanke, Thomas; Kaiser, Astrid; Lamers, Christina; Werz, Oliver; Schneider, Gisbert; Schubert-Zsilavecz, Manfred
Author(s) at UniBasel Lamers, Christina
Year 2014
Title Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR).
Journal Bioorganic & medicinal chemistry
Volume 22
Number 8
Pages / Article-Number 2447-60
Mesh terms Binding Sites; Ligands; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Receptors, Cytoplasmic and Nuclear, agonists, metabolism; Structure-Activity Relationship; ortho-Aminobenzoates, chemical synthesis, chemistry, metabolism
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.

ISSN/ISBN 1464-3391
Full Text on edoc
Digital Object Identifier DOI 10.1016/j.bmc.2014.02.053
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/24685112
   

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