Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)
Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)
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DOI：
10.1021/jm500889f
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发表时间：
2014-09-25
影响因子：
7.3
通讯作者：
Fiorucci, Stefano
中科院分区：
文献类型：
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作者：
Sepe, Valentina;Renga, Barbara;Fiorucci, Stefano
胆汁酸是与核受体 FXR 和 G 蛋白偶联受体 1 (GP-BAR1/TGR5) 相互作用的信号分子。 GP-BAR1 是治疗脂肪性肝炎、2 型糖尿病和肥胖症的有前景的药理学靶点。内源性胆汁酸和目前可用的半合成胆汁酸对 GP-BAR1 和 FXR 的选择性较差。因此，在本研究中，我们围绕 UDCA（一种临床使用的缺乏 FXR 激动剂活性的胆汁酸）的结构进行了研究，以开发一个大家族的侧链修饰 3 α,7 β-二羟基胆烷，选择性激活 GP-BAR1。体内和体外药理学评价表明，给予化合物16选择性增加小肠中GP-BAR1靶点胰高血糖素原1的表达，而对肝脏中FXR靶基因没有影响。此外，化合物 16 导致胆汁淤积啮齿动物模型中胆汁酸池的显着重塑。这些数据表明 UDCA 是生成 GP-BAR1 新型选择性甾体配体的有用支架。
Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3 alpha,7 beta-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of proglucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.