Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3α,7β-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1

Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1) / Sepe, Valentina; Barbara, Renga; Festa, Carmen; Claudio, D’Amore; Masullo, Dario; Sabrina, Cipriani; Di Leva, Francesco Saverio; Maria Chiara, Monti; Novellino, Ettore; Limongelli, Vittorio; Zampella, Angela; Stefano, Fiorucci. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 57:18(2014), pp. 7687-7701. [10.1021/jm500889f]

Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)

SEPE, VALENTINA
Primo
;
FESTA, CARMEN;MASULLO, DARIO;Di Leva, Francesco Saverio;Maria Chiara Monti;NOVELLINO, ETTORE;LIMONGELLI, VITTORIO;ZAMPELLA, ANGELA
;
2014

Abstract

Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3α,7β-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1
2014
Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1) / Sepe, Valentina; Barbara, Renga; Festa, Carmen; Claudio, D’Amore; Masullo, Dario; Sabrina, Cipriani; Di Leva, Francesco Saverio; Maria Chiara, Monti; Novellino, Ettore; Limongelli, Vittorio; Zampella, Angela; Stefano, Fiorucci. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 57:18(2014), pp. 7687-7701. [10.1021/jm500889f]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/586249
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