Nomura Sayaka, Endo-Umeda Kaori, Makishima Makoto, Hashimoto Yuichi, Ishikawa Minoru
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
ChemMedChem. 2016 Oct 19;11(20):2347-2360. doi: 10.1002/cmdc.201600305. Epub 2016 Sep 30.
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.
肝脏X受体（LXR）激动剂是通过诱导ABCA1（ATP结合盒转运体A1）基因表达来治疗动脉粥样硬化的候选药物，ABCA1基因表达有助于逆向胆固醇转运（RCT）以及肝脏和肠道中的胆固醇流出。然而，LXR激动剂也会诱导参与脂肪生成的基因表达，如SREBP-1c（固醇调节元件结合蛋白1c）和FAS（脂肪酸合酶），从而导致血浆和肝脏甘油三酯（TG）水平出现不良升高。最近的研究表明，LXRα参与肝脏脂肪生成，而选择性激活LXRβ可改善小鼠的RCT。因此，LXRβ选择性激动剂有望在不增加血浆或肝脏TG水平的情况下改善动脉粥样硬化。然而，两种LXR亚型α/β的配体结合域具有高度的序列同一性，很少有LXR配体表现出亚型选择性。在本研究中，我们鉴定出一种四氯邻苯二甲酰亚胺类似物作为LXRβ选择性激动剂。通过结构优化得到了（E）-4,5,6,7-四氯-2-（2-苯乙烯基苯基）异吲哚啉-1,3-二酮（24 a），其在报告基因检测中表现出强效且选择性的LXRβ激动活性。在结合实验中，化合物24 a与LXRβ的结合优先于LXRα。它还能在细胞中诱导ABCA1 mRNA的表达，但不会诱导SREBP-1c mRNA的表达。化合物24 a似乎是一种有前景的先导化合物，可用于开发治疗动脉粥样硬化的治疗药物，且不会产生LXRα/β双重激动剂所诱导的副作用。
