Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators.
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.
Institute of Molecular and Cellular Biosciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Sayaka
S
Nomura
Nihon University School of Medicine , 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
Kaori
K
Endo-Umeda
Institute of Molecular and Cellular Biosciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Atsushi
A
Aoyama
Nihon University School of Medicine , 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
Makoto
M
Makishima
Institute of Molecular and Cellular Biosciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Yuichi
Y
Hashimoto
Institute of Molecular and Cellular Biosciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Minoru
M
Ishikawa
Liver X receptor; inhibition of interleukin-6 level; styrylphenylphthalimide; transrepression