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

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 LXR alpha contributes to lipogenesis in liver, and selective LXR beta activation improves RCT in mice. Therefore, LXR beta-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 alpha/beta share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXR beta-selective agonist. Structural development led to (E)-4,5,6,7-tetrachloro-2-(2-styrylphenyl)isoindoline-1,3-dione (24a), which shows potent and selective LXR beta agonistic activity in reporter gene assays. In binding assays, compound 24a bound to LXR beta preferentially over LXR alpha. It also induced the expression of ABCA1 mRNA but not SREBP-1c mRNA in cells. Compound 24a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXR alpha/beta dual agonists.