title: Extending the structure-activity relationship of anthranilic acid derivatives as farnesoid X receptor modulators: development of a highly potent partial farnesoid X receptor agonist.
abstract: 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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt , Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Merk
authors.forename: Christina
authors.initials: C
authors.lastname: Lamers
authors.forename: Khalil
authors.initials: K
authors.lastname: Ahmad
authors.forename: Roberto
authors.initials: R
authors.lastname: Carrasco Gomez
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D000818:Animals; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D062367:ortho-Aminobenzoates; D000099150:Receptor, Farnesoid X-Activated; C031385:anthranilic acid