Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands.

@article{Festa2014ExploitationOC,
  title={Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands.},
  author={Carmen Festa and B. Renga and C. D’Amore and V. Sepe and C. Finamore and S. De Marino and Adriana Carino and S. Cipriani and M. Monti and A. Zampella and S. Fiorucci},
  journal={Journal of medicinal chemistry},
  year={2014},
  volume={57 20},
  pages={
          8477-95
        }
}
Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. In the present study, we describe a novel library of semisynthetic… Expand
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TLDR
This compound when administered in vivo exerts a robust FXR agonistic activity increasing the liver expression of FXR-target genes including SHP, BSEP, OSTα, and FGF21, while represses the expression of CYP7A1 gene that is negatively regulated by FXR, resulting in a significant reshaping of BA pool in mouse. Expand
Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands
TLDR
A new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPB BAR1 were assayed, resulting in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity. Expand
Epoxide functionalization on cholane side chains in the identification of G-protein coupled bile acid receptor (GPBAR1) selective agonists
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To the best of the knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1, and a small library of cholane derivatives, endowed with dual FXR agonism/GPB AR1 antagonism are investigated. Expand
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3β-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3α-epimer by hepatic metabolism
TLDR
It is found that only the 3β-hydroxy epimer of OCA possesses significant activity to FXR in hepatic cells and mice, and 3,7-dehydroobeticholic acid is a potent GPBAR1 agonist. Expand
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TLDR
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Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists.
TLDR
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TLDR
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Chemistry and Pharmacology of GPBAR1 and FXR Selective Agonists, Dual Agonists, and Antagonists.
TLDR
The most recent acquisition on natural, semisynthetic, and synthetic steroidal and nonsteroidal ligands, able to interact with FXR and GPBAR1 are summarized. Expand
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