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Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR).
Bioorg Med Chem. 2014 Apr 15; 22(8):2447-60.BM

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+Show Affiliations

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.Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.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.Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany.Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland.Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24685112

Citation

Merk, Daniel, et al. "Anthranilic Acid Derivatives as Novel Ligands for Farnesoid X Receptor (FXR)." Bioorganic & Medicinal Chemistry, vol. 22, no. 8, 2014, pp. 2447-60.
Merk D, Gabler M, Gomez RC, et al. Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR). Bioorg Med Chem. 2014;22(8):2447-60.
Merk, D., Gabler, M., Gomez, R. C., Flesch, D., Hanke, T., Kaiser, A., Lamers, C., Werz, O., Schneider, G., & Schubert-Zsilavecz, M. (2014). Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR). Bioorganic & Medicinal Chemistry, 22(8), 2447-60. https://doi.org/10.1016/j.bmc.2014.02.053
Merk D, et al. Anthranilic Acid Derivatives as Novel Ligands for Farnesoid X Receptor (FXR). Bioorg Med Chem. 2014 Apr 15;22(8):2447-60. PubMed PMID: 24685112.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR). AU - Merk,Daniel, AU - Gabler,Matthias, AU - Gomez,Roberto Carrasco, AU - Flesch,Daniel, AU - Hanke,Thomas, AU - Kaiser,Astrid, AU - Lamers,Christina, AU - Werz,Oliver, AU - Schneider,Gisbert, AU - Schubert-Zsilavecz,Manfred, Y1 - 2014/03/15/ PY - 2013/12/04/received PY - 2014/02/24/revised PY - 2014/02/28/accepted PY - 2014/4/2/entrez PY - 2014/4/2/pubmed PY - 2014/12/15/medline KW - Bile acids KW - Farnesoid X receptor KW - Glucose homeostasis KW - Metabolic disorder KW - Nuclear receptor SP - 2447 EP - 60 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 22 IS - 8 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/24685112/Anthranilic_acid_derivatives_as_novel_ligands_for_farnesoid_X_receptor__FXR__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(14)00168-0 DB - PRIME DP - Unbound Medicine ER -