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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.
