Bile acids exert genomic and non-genomic effects by interacting with membrane G-protein coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions, thus GP-BAR1/FXR agonists, by enhancing the biological response, represent an innovative strategy for the treatment of entero-endocrine disorders. UDCA (ursodeoxycholic acid), present in human bile at low concentrations, has been shown effective in biliary and liver diseases and is now considered as the first-line treatment for primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and intrahepatic cholestasis of pr egnancy (ICP). UDCA is the 7-beta hydroxy epimer of CDCA and, despite its pharmacological profile, UDCA is not a FXR agonist and its mechanism of action remains unclear and still subjected to intense scientific debates. Indeed UDCA is considered a safety molecule with a clinical history with minimal side effects, also when used in large doses. In this context we decided to manipulate UDCA chemical scaffold obtaining a large library of derivatives. This research work resulted in the identification, for the first time, of several UDCA analogues endowed with bile acid receptors agonistic profile.

Discovery of UDCA derivatives as new modulators of bile acid receptors

FINAMORE, CLAUDIA;SEPE, VALENTINA;FESTA, CARMEN;Francesco Saverio Di Leva;LIMONGELLI, VITTORIO;NOVELLINO, ETTORE;ZAMPELLA, ANGELA;
2014

Abstract

Bile acids exert genomic and non-genomic effects by interacting with membrane G-protein coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions, thus GP-BAR1/FXR agonists, by enhancing the biological response, represent an innovative strategy for the treatment of entero-endocrine disorders. UDCA (ursodeoxycholic acid), present in human bile at low concentrations, has been shown effective in biliary and liver diseases and is now considered as the first-line treatment for primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and intrahepatic cholestasis of pr egnancy (ICP). UDCA is the 7-beta hydroxy epimer of CDCA and, despite its pharmacological profile, UDCA is not a FXR agonist and its mechanism of action remains unclear and still subjected to intense scientific debates. Indeed UDCA is considered a safety molecule with a clinical history with minimal side effects, also when used in large doses. In this context we decided to manipulate UDCA chemical scaffold obtaining a large library of derivatives. This research work resulted in the identification, for the first time, of several UDCA analogues endowed with bile acid receptors agonistic profile.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/587633
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