Exploitation of Cholane Scaffold for the Discovery of Potent and Selective Farnesoid X Receptor (FXR) and G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1) Ligands
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- 作者：Carmen Festa ; Barbara Renga ; Claudio D鈥橝more ; Valentina Sepe ; Claudia Finamore ; Simona De Marino ; Adriana Carino ; Sabrina Cipriani ; Maria Chiara Monti ; Angela Zampella ; Stefano Fiorucci
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：October 23, 2014
- 年：2014
- 卷：57
- 期：20
- 页码：8477-8495
- 全文大小：743K
- ISSN：1520-4804
文摘
Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. In the present study, we describe a novel library of semisynthetic bile acid derivatives obtained by modifications on the cholane scaffold. The pharmacological characterization of this library led to the discovery of 7伪-hydroxy-5尾-cholan-24-sulfate (7), 6尾-ethyl-3伪,7尾-dihydroxy-5尾-cholan-24-ol (EUDCOH, 26), and 6伪-ethyl-3伪, 7伪-dihydroxy-24-nor-5尾-cholan-23-ol (NorECDCOH, 30) as novel ligands for FXR and GP-BAR1 that might hold utility in the treatment of FXR and GP-BAR1 mediated disorders.