title: Anthranilic acid derivatives as nuclear receptor modulators--development of novel PPAR selective and dual PPAR/FXR ligands.
abstract: Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany. Electronic address: merk@pharmchem.uni-frankfurt.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Merk
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lamers
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Weber
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Flesch
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gabler
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000737:chemistry; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D062367:ortho-Aminobenzoates; D000099150:Receptor, Farnesoid X-Activated; C031385:anthranilic acid
keywords: Farnesoid X receptor (FXR); Lipid metabolism; Metabolic disorders; Nuclear receptors; Peroxisome proliferator activated receptors (PPAR)