Design, synthesis, and biological evaluation of novel transrepression- selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11- methylene-6 H-dibenz[ b, e ]azepin-6-one skeleton

Atsushi Aoyama, Kaori Endo-Umeda, Kenji Kishida, Kenji Ohgane, Tomomi Noguchi-Yachide, Hiroshi Aoyama, Minoru Ishikawa, Hiroyuki Miyachi, Makoto Makishima, Yuichi Hashimoto

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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.

Original languageEnglish
Pages (from-to)7360-7377
Number of pages18
JournalJournal of Medicinal Chemistry
Volume55
Issue number17
DOIs
Publication statusPublished - Sep 13 2012

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Aoyama, A., Endo-Umeda, K., Kishida, K., Ohgane, K., Noguchi-Yachide, T., Aoyama, H., Ishikawa, M., Miyachi, H., Makishima, M., & Hashimoto, Y. (2012). Design, synthesis, and biological evaluation of novel transrepression- selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11- methylene-6 H-dibenz[ b, e ]azepin-6-one skeleton. Journal of Medicinal Chemistry, 55(17), 7360-7377. https://doi.org/10.1021/jm3002394