1. Academic Validation
  2. 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

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

  • J Med Chem. 2014 Oct 23;57(20):8477-95. doi: 10.1021/jm501273r.
Carmen Festa 1 Barbara Renga Claudio D'Amore Valentina Sepe Claudia Finamore Simona De Marino Adriana Carino Sabrina Cipriani Maria Chiara Monti Angela Zampella Stefano Fiorucci
Affiliations

Affiliation

  • 1 Department of Pharmacy, University of Naples "Federico II" , Via D. Montesano 49, I-80131 Naples, Italy.
Abstract

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 bile acid derivatives obtained by modifications on the cholane scaffold. The pharmacological characterization of this library led to the discovery of 7α-hydroxy-5β-cholan-24-sulfate (7), 6β-ethyl-3α,7β-dihydroxy-5β-cholan-24-ol (EUDCOH, 26), and 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (NorECDCOH, 30) as novel ligands for FXR and GP-BAR1 that might hold utility in the treatment of FXR and GP-BAR1 mediated disorders.

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