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Discovery of ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl)ureidyl derivatives as selective non-steroidal agonists of the G-protein coupled bile acid receptor-1
- Source :
- Scientific Reports, Vol 9, Iss 1, Pp 1-9 (2019), Scientific Reports
- Publication Year :
- 2019
-
Abstract
- The G-protein bile acid receptor 1 (GPBAR1) has emerged in the last decade as prominent target for the treatment of metabolic and inflammatory diseases including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. To date numerous bile acid derivatives have been identified as GPBAR1 agonists, however their clinical application is hampered by the lack of selectivity toward the other bile acid receptors. Therefore, non-steroidal GPBAR1 ligands able to selectively activate the receptor are urgently needed. With this aim, we here designed, synthesized and biologically evaluated ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl) urea derivatives as novel potent GPBAR1 agonists. Particularly, compounds 9 and 10 induce the mRNA expression of the GPBAR1 target gene pro-glucagon and show high selectivity over the other bile acid receptors FXR, LXRα, LXRβ and PXR, and the related receptors PPARα and PPARγ. Computational studies elucidated the binding mode of 10 to GPBAR1, providing important structural insights for the design of non-steroidal GPBAR1 agonists. The pharmacokinetic properties of 9 and 10 suggest that the ((1,2,4-oxadiazol-5-yl)pyrrolidin-3-yl)ureydil scaffold might be exploited to achieve effective drug candidates to treat GPBAR1 related disorders.
- Subjects :
- 0301 basic medicine
Drug
medicine.drug_class
media_common.quotation_subject
lcsh:Medicine
Pharmacology
Ligands
Article
Receptors, G-Protein-Coupled
Bile Acids and Salts
ADME Molecular docking
03 medical and health sciences
Bile acids, G-protein bile acid receptor 1, Metabolic diseases, Medicinal Chemistry, Molecular modelling
0302 clinical medicine
Pharmacokinetics
Non-alcoholic Fatty Liver Disease
medicine
Bile
Humans
Urea
Obesity
Receptor
lcsh:Science
media_common
Pregnane X receptor
Multidisciplinary
Bile acid
Chemistry
HEK 293 cells
lcsh:R
medicine.disease
G protein-coupled bile acid receptor
030104 developmental biology
HEK293 Cells
Diabetes Mellitus, Type 2
lcsh:Q
Steatohepatitis
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Scientific Reports, Vol 9, Iss 1, Pp 1-9 (2019), Scientific Reports
- Accession number :
- edsair.doi.dedup.....689fa23093caa4b9a3bb7cc957d9f651