52956-63-5Relevant academic research and scientific papers
Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR)
Merk, Daniel,Gabler, Matthias,Gomez, Roberto Carrasco,Flesch, Daniel,Hanke, Thomas,Kaiser, Astrid,Lamers, Christina,Werz, Oliver,Schneider, Gisbert,Schubert-Zsilavecz, Manfred
, p. 2447 - 2460 (2014/05/06)
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.
Extending the structure-activity relationship of anthranilic acid derivatives as farnesoid x receptor modulators: Development of a highly potent partial farnesoid x receptor agonist
Merk, Daniel,Lamers, Christina,Ahmad, Khalil,Carrasco Gomez, Roberto,Schneider, Gisbert,Steinhilber, Dieter,Schubert-Zsilavecz, Manfred
, p. 8035 - 8055 (2014/12/10)
The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.
