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

研究成果: Article査読

37 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)7360-7377
ページ数18
ジャーナルJournal of Medicinal Chemistry
55
17
DOI
出版ステータスPublished - 2012 9 13
外部発表はい

ASJC Scopus subject areas

  • 分子医療
  • 創薬

フィンガープリント

「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」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

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