title: Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR).
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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. Electronic address: merk@pharmchem.uni-frankfurt.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Merk
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gabler
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany; Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland.
authors.forename: Roberto Carrasco
authors.initials: RC
authors.lastname: Gomez
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Flesch
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hanke
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kaiser
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lamers
authors.affiliation: Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D001665:Binding Sites; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D062367:ortho-Aminobenzoates; D000099150:Receptor, Farnesoid X-Activated; C031385:anthranilic acid
keywords: Bile acids; Farnesoid X receptor; Glucose homeostasis; Metabolic disorder; Nuclear receptor