Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties.
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.
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Daniel
D
Flesch
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Matthias
M
Gabler
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Andreas
A
Lill
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Roberto Carrasco
RC
Gomez
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Ramona
R
Steri
Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog Weg 1-5/10, 8093 Zürich, Switzerland.
Gisbert
G
Schneider
Institute for Pharmaceutical und Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Holger
H
Stark
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Manfred
M
Schubert-Zsilavecz
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany. Electronic address: merk@pharmchem.uni-frankfurt.de.
Daniel
D
Merk
D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015870:Gene Expression; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D006868:Hydrolysis; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D007555:Isoxazoles; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064
FXR agonists; Farnesoid X receptor; Fluorescent FXR ligand; Metabolic disorders; Nuclear receptors