title: Discovery and optimization of non-steroidal FXR agonists from natural product-like libraries.
abstract: 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.
authors.affiliation: 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.
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: A J
authors.initials: AJ
authors.lastname: Roecker
authors.forename: Robert
authors.initials: R
authors.lastname: Hughes
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Pfefferkorn
mesh_terms: D001578:Benzopyrans / Q000138:chemical synthesis; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001685:Biological Factors; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000138:chemical synthesis / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008024:Ligands; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000819:agonists* / Q000138:chemical synthesis / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001578:Benzopyrans; D001647:Bile Acids and Salts; D001685:Biological Factors; D002784:Cholesterol; D004268:DNA-Binding Proteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated