2. Academic Validation
  3. Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties

Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties

  • Bioorg Med Chem. 2015 Jul 1;23(13):3490-8. doi: 10.1016/j.bmc.2015.04.035.
Daniel Flesch 1,  Matthias Gabler 1,  Andreas Lill 1,  Roberto Carrasco Gomez 1,  Ramona Steri 1,  Gisbert Schneider 2,  Holger Stark 3,  Manfred Schubert-Zsilavecz 1,  Daniel Merk 4
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
  • 2 Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog Weg 1-5/10, 8093 Zürich, Switzerland.
  • 3 Institute for Pharmaceutical und Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • 4 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany. Electronic address: merk@pharmchem.uni-frankfurt.de.
PMID: 25934227 DOI: 10.1016/j.bmc.2015.04.035
Abstract

The ligand activated transcription factor farnesoid X receptor (FXR) is a crucial regulator of several metabolic and inflammatory pathways and its activation by agonistic ligands seems a valuable therapeutic approach for many disorders. Most known non-steroidal FXR agonists however, have limitations that hinder their clinical development and novel FXR ligands are required. Evaluation of the co-crystal structures of the widely used FXR Agonist GW4064 and related compounds in complex with the FXR ligand binding domain indicated that their disubstituted isoxazole moiety is especially relevant for FXR activation. By investigation of GW4064-fragments missing the aromatic tail, we discovered a highly potent and soluble partial FXR Agonist (14, ST-1892) as well as a fluorescent FXR ligand (15) as potential pharmacological tool.

Keywords

FXR agonists; Farnesoid X receptor; Fluorescent FXR ligand; Metabolic disorders; Nuclear receptors.

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