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.

Di Leva FS; Festa C; Carino A; De Marino S; Marchianò S; Di Marino D; Finamore C; Monti MC; Zampella A; Fiorucci S; Limongelli V

doi:10.1038/s41598-019-38840-z

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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.

Di Leva FS Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
Festa C Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
Carino A Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia, Italy.
De Marino S Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
Marchianò S Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia, Italy.
Di Marino D Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute of Computational Science - Center for Computational Medicine in Cardiology, Via G. Buffi 13, CH-6900, Lugano, Switzerland.
Finamore C Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
Monti MC Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, Salerno, Italy.
Zampella A Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
Fiorucci S Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia, Italy.
Limongelli V Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy. vittoriolimongelli@gmail.com.

2019-02-23

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Scientific reports. - 2019

Non-alcoholic Fatty Liver Disease

English 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.

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