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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- 作者：Valentina Sepe ; Barbara Renga ; Carmen Festa ; Claudio D鈥橝more ; Dario Masullo ; Sabrina Cipriani ; Francesco Saverio Di Leva ; Maria Chiara Monti ; Ettore Novellino ; Vittorio Limongelli ; Angela Zampella ; Stefano Fiorucci
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：September 25, 2014
- 年：2014
- 卷：57
- 期：18
- 页码：7687-7701
- 全文大小：666K
- ISSN：1520-4804
文摘
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伪,7尾-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 pro-glucagon 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.