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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2015 Aug 20

PMID 26288691

Citations 8

Authors

Sayaka Nomura

Kaori Endo-Umeda

Atsushi Aoyama

Makoto Makishima

Yuichi Hashimoto

Minoru Ishikawa

Affiliations

Soon will be listed here.

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.

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