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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)
- Source :
- Journal of Medicinal Chemistry. 57:7687-7701
- Publication Year :
- 2014
- Publisher :
- American Chemical Society (ACS), 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.
- Subjects :
- Models, Molecular
Agonist
Protein Conformation
medicine.drug_class
nuclear receptors
Receptors, G-Protein-Coupled
Substrate Specificity
Cholestasis
medicinal chemistry
Drug Discovery
medicine
Humans
Receptor
Bile acid
Chemistry
Ursodeoxycholic Acid
Hep G2 Cells
medicine.disease
G protein-coupled bile acid receptor
Small intestine
Ursodeoxycholic acid
nuclear receptors, medicinal chemistry
HEK293 Cells
medicine.anatomical_structure
Biochemistry
Nuclear receptor
Molecular Medicine
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....122d33ada5505eb850da349ac70e52a7