Hyodeoxycholic acid derivatives as liver X receptor α and G-protein-coupled bile acid receptor agonists.
Hyodeoxycholic acid derivatives as liver X receptor α and G-protein-coupled bile acid receptor agonists.
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DOI：
10.1038/srep43290
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发表时间：
2017-02-24
影响因子：
4.6
通讯作者：
Zampella A
中科院分区：
文献类型：
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作者：
De Marino S;Carino A;Masullo D;Finamore C;Marchianò S;Cipriani S;Di Leva FS;Catalanotti B;Novellino E;Limongelli V;Fiorucci S;Zampella A
胆汁酸因其在治疗人类疾病中的潜力而被广泛研究。肝X受体（LXR），由氧化固醇和二级胆汁酸命名的猪去氧胆酸（HDCA）激活，已被发现在调节脂质稳态在哺乳动物中是必不可少的。不幸的是，LXRα激活脂肪生成酶，导致脂质在肝脏中积聚。除了LXR之外，HDCA还显示出作为GPBAR 1的配体起作用，GPBAR 1是次级胆汁酸的G蛋白偶联受体，其活化代表了一种有希望的肝脏脂肪变性方法。在本研究中，我们报告了一个库HDCA衍生物赋予两个受体的调节活性。HDCA部分的先导优化由两个靶标结合位点的结构信息合理驱动，药理学表征结果允许鉴定对LXRα和GPBAR 1具有选择性激动活性的猪脱氧胆烷衍生物，特别是鉴定强效双重LXRα/GPBAR 1激动剂的第一个实例。新的化学实体可能在治疗血脂异常疾病中具有实用性。
Bile acids are extensively investigated for their potential in the treatment of human disorders. The liver X receptors (LXRs), activated by oxysterols and by a secondary bile acid named hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In addition to LXRs, HDCA has been also shown to function as ligand for GPBAR1, a G protein coupled receptor for secondary bile acids whose activation represents a promising approach to liver steatosis. In the present study, we report a library of HDCA derivatives endowed with modulatory activity on the two receptors. The lead optimization of HDCA moiety was rationally driven by the structural information on the binding site of the two targets and results from pharmacological characterization allowed the identification of hyodeoxycholane derivatives with selective agonistic activity toward LXRα and GPBAR1 and notably to the identification of the first example of potent dual LXRα/GPBAR1 agonists. The new chemical entities might hold utility in the treatment of dyslipidemic disorders.