Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators

Sayaka Nomura, Kaori Endo-Umeda, Atsushi Aoyama, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due to LXR-mediated transrepression, whereas side effects are caused by activation of LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit transrepression activity should exhibit anti-inflammatory properties with fewer side effects. Here, we synthesized a series of styrylphenylphthalimide analogues and evaluated their structure-activity relationships focusing on LXRs-transactivating-agonistic/antagonistic activities and transrepressional activity. Among the compounds examined, 17l showed potent LXR-transrepressional activity with high selectivity over transactivating activity and did not show characteristic side effects of LXR-transactivating agonists in cells. This representative compound, 17l, was confirmed to have LXR-dependent transrepressional activity and to bind directly to LXRβ. Compound 17l should be useful not only as a chemical tool for studying the biological functions of LXRs transrepression but also as a candidate for a safer agent to treat inflammatory diseases.

Original languageEnglish
Pages (from-to)902-907
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume6
Issue number8
DOIs
Publication statusPublished - 2015 Aug 13
Externally publishedYes

Keywords

  • Liver X receptor
  • inhibition of interleukin-6 level
  • styrylphenylphthalimide
  • transrepression

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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