Pellicciari Roberto, Costantino Gabriele, Camaioni Emidio, Sadeghpour Bahman M, Entrena Antonio, Willson Timothy M, Fiorucci Stefano, Clerici Carlo, Gioiello Antimo
Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
J Med Chem. 2004 Aug 26;47(18):4559-69. doi: 10.1021/jm049904b.
The farnesoid X receptor (FXR) is activated by endogenous bile acids (BAs) and plays a variety of physiological roles related to modulation of gene transcription. In particular, FXR positively regulates the cholesterol catabolism while feedback inhibits the BA synthesis by repressing the expression of the CYP7A and CYP8B genes. We have previously shown that 6alpha-ethyl-CDCA (6ECDCA) is a potent and selective FXR agonist. In this paper we report an extensive structure-activity relationship for a series of synthetic bile acids. Our results indicate that the 6alpha position plays a fundamental role in determining affinity and that the side chain of BA is amenable to a variety of chemical modification. Although none of the new derivatives is more potent than 6ECDCA, we show here that a wide variability in efficacy, from full agonists to partial antagonists, can be obtained.
法尼酯X受体（FXR）可被内源性胆汁酸（BA）激活，并在与基因转录调控相关的多种生理过程中发挥作用。特别是，FXR正向调节胆固醇分解代谢，同时通过抑制CYP7A和CYP8B基因的表达反馈抑制BA合成。我们之前已经表明，6α-乙基-鹅去氧胆酸（6ECDCA）是一种强效且选择性的FXR激动剂。在本文中，我们报告了一系列合成胆汁酸广泛的构效关系。我们的结果表明，6α位在决定亲和力方面起着根本性作用，并且BA的侧链适合进行多种化学修饰。尽管没有一种新衍生物比6ECDCA更有效，但我们在此表明，可以获得从完全激动剂到部分拮抗剂的广泛效力变化。
