Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors
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- 作者：Claudio D’Amore ; Francesco Saverio Di Leva ; Valentina Sepe ; Barbara Renga ; Chiara Del Gaudio ; Maria Valeria D’Auria ; Angela Zampella ; Stefano Fiorucci ; Vittorio Limongelli
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：February 13, 2014
- 年：2014
- 卷：57
- 期：3
- 页码：937-954
- 全文大小：755K
- ISSN：1520-4804
文摘
Bile acids exert genomic and nongenomic effects by interacting with membrane G-protein-coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions; thus, GP-BAR1/FXR dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.