Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)-Selective Agonists

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

研究成果: Article査読

15 被引用数 (Scopus)


Liver X receptor (LXR) agonists are candidates for the treatment of atherosclerosis via induction of ABCA1 (ATP-binding cassette A1) gene expression, which contributes to reverse cholesterol transport (RCT) and to cholesterol efflux from the liver and intestine. However, LXR agonists also induce genes involved in lipogenesis, such as SREBP-1c (sterol regulatory binding element protein 1c) and FAS (fatty acid synthase), thereby causing an undesirable increase in plasma and hepatic triglyceride (TG) levels. Recent studies indicate that LXRα contributes to lipogenesis in liver, and selective LXRβ activation improves RCT in mice. Therefore, LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. However, the ligand-binding domains in the two LXR isoforms α/β share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXRβ-selective agonist. Structural development led to (E)-4,5,6,7-tetrachloro-2-(2-styrylphenyl)isoindoline-1,3-dione (24 a), which shows potent and selective LXRβ agonistic activity in reporter gene assays. In binding assays, compound 24 a bound to LXRβ preferentially over LXRα. It also induced the expression of ABCA1 mRNA but not SREBP-1c mRNA in cells. Compound 24 a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXRα/β dual agonists.

出版ステータスPublished - 2016 10 19

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 薬理学
  • 創薬
  • 薬理学、毒性学および薬学(全般)
  • 有機化学


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