2. Academic Validation
  3. Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators

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

  • ACS Med Chem Lett. 2015 Jul 13;6(8):902-7. doi: 10.1021/acsmedchemlett.5b00170.
Sayaka Nomura 1,  Kaori Endo-Umeda 2,  Atsushi Aoyama 1,  Makoto Makishima 2,  Yuichi Hashimoto 1,  Minoru Ishikawa 1
Affiliations

Affiliations

  • 1 Institute of Molecular and Cellular Biosciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 Nihon University School of Medicine , 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
PMID: 26288691 DOI: 10.1021/acsmedchemlett.5b00170
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.

Keywords

Liver X receptor; inhibition of interleukin-6 level; styrylphenylphthalimide; transrepression.

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