Targeting Bile Acid Receptors: Discovery of a Potent and Selective Farnesoid X Receptor Agonist as a New Lead in the Pharmacological Approach to Liver Diseases.
作者： Carmen Festa , Simona De Marino , Adriana Carino , Valentina Sepe , Silvia Marchianò
关键词: Cholesterol 7 alpha-hydroxylase 、 Agonist 、 Farnesoid X receptor 、 G protein-coupled bile acid receptor 、 Biochemistry 、 Receptor 、 Nuclear receptor 、 Biology 、 Pharmacology 、 Transactivation 、 Bile acid
摘要: Bile acid receptors represent well-defined targets for the development of novel therapeutic approaches to metabolic and inflammatory diseases. In present study, we report generation C-3 modified 6-ethylcholane. The pharmacological characterization molecular docking studies structure-activity rationalization, allowed identification 3-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic (compound 2), a potent selective FXR agonist with nanomolar potency in transactivation assay high efficacy recruitment SRC-1 co-activator peptide Alfa Screen assay. vitro, compound 2 was completely inactive towards common off-targets such as nuclear PPAR, PPAR, LXR, LXRand membrane G-coupled bile receptor, GPBAR1. This when administered vivo exerts robust agonistic activity increasing liver expression FXR-target genes including SHP, BSEP, OST FgF21, while represses that are negatively regulated by (CYP7A1), collectively these effects result significant reshaping pool mouse. summary, could promising candidate drug disorders
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