کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2027529 | 1542703 | 2016 | 9 صفحه PDF | دانلود رایگان |
• Modification on bile acids resulted in the identification of FXR/GPBAR1 modulators.
• All derivatives were evaluated on FXR and GPBAR1 transactivation.
• Cholanoic acids are the first example of GPBAR1 antagonists.
• Cholanoic acids are novel chemical probes in FXR mediated liver disorders.
Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1.
Journal: Steroids - Volume 105, January 2016, Pages 59–67