title: Design, synthesis, and biological evaluation of novel transrepression-selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one skeleton.
abstract: To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity of the 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and transactivational activity. Structural modification of 10 based on the reported X-ray crystal structure of the LXR ligand-binding domain led to a series of compounds, of which almost all exhibited transrepressional activity at 1 or 10 μM but showed no transactivational activity even at 30 μM. Among the compounds obtained, 18 and 22 were confirmed to have LXR-dependent transrepressional activity by using peritoneal macrophages from wild-type and LXR-null mice. A newly developed fluorescence polarization assay indicated that they bind directly to LXRα. Next, further structural modification was performed with the guidance of docking simulations with LXRα, focusing on enhancing the binding of the ligands with LXRα through the introduction of substituents or heteroatom(s). Among the compounds synthesized, compound 48, bearing a hydroxyl group, showed potent, selective, and dose-dependent transrepressional activity.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Aoyama
authors.forename: Kaori
authors.initials: K
authors.lastname: Endo-Umeda
authors.forename: Kenji
authors.initials: K
authors.lastname: Kishida
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohgane
authors.forename: Tomomi
authors.initials: T
authors.lastname: Noguchi-Yachide
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoyama
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D018360:Crystallography, X-Ray; D003989:Dibenzoxazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D008024:Ligands; D000071518:Liver X Receptors; D009682:Magnetic Resonance Spectroscopy; D057093:Orphan Nuclear Receptors / Q000737:chemistry*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D003989:Dibenzoxazepines; D008024:Ligands; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors