Nicolaou K C, Evans Ronald M, Roecker A J, Hughes Robert, Downes Michael, Pfefferkorn Jeffery A
Department of Chemistry, Skaggs Institute for Chemical Biology, Scripps Research Institute, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
Org Biomol Chem. 2003 Mar 21;1(6):908-20.
The efficient regulation of cholesterol biosynthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. Herein, we describe the development of four novel classes of potent FXR activators originating from natural product-like libraries. Initial screening of a 10,000-membered, diversity-orientated library of benzopyran containing small molecules for FXR activation utilizing a cell-based reporter assay led to the identification of several lead compounds possessing low micromolar activity (EC50's = 5-10 microM). These compounds were systematically optimized employing parallel solution-phase synthesis and solid-phase synthesis to provide four classes of compounds that potently activate FXR. Two series of compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds may find future utility as chemical tools in studies aimed at further defining the physiological role of FXR and discovering potential therapeutic agents for the treatment of diseases linked to cholesterol and bile acid metabolism and homeostasis.
胆固醇生物合成、代谢、摄取及转运的有效调节是脂质稳态的重要组成部分。法尼酯X受体（FXR）是胆固醇代谢的主要产物——胆汁酸的转录传感器。因此，开发强效、选择性的FXR小分子激动剂、部分激动剂和拮抗剂将是进一步阐明FXR生理学的重要一步。在此，我们描述了源自类天然产物文库的四类新型强效FXR激活剂的开发。利用基于细胞的报告基因检测法，对一个包含10000个成员的、以多样性为导向的含苯并吡喃小分子文库进行FXR激活的初步筛选，鉴定出了几种具有低微摩尔活性（EC50 = 5 - 10 microM）的先导化合物。通过平行溶液相合成和固相合成对这些化合物进行系统优化，得到了四类能有效激活FXR的化合物。带有二苯乙烯或联芳基部分的两个系列化合物包含了在基于细胞的检测中迄今报道的最有效的FXR激动剂成员。这些化合物未来可能作为化学工具，用于进一步确定FXR生理作用以及发现与胆固醇和胆汁酸代谢及稳态相关疾病潜在治疗药物的研究中。
