Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators

Ruchika Sharma, David Prichard, Ferenc Majer, Anne Marie Byrne, Dermot Kelleher, Aideen Long, John F. Gilmer

Research output: Contribution to journalArticlepeer-review


Ursodeoxycholic acid (UDCA) is used for the treatment of hepatic inflammatory diseases. Recent studies have shown that UDCAs biological effects are partly glucocorticoid receptor (GR) mediated. UDCA derivatives were synthesized and screened for ability to induce GR translocation in a high content analysis assay using the esophageal cancer SKGT-4 cell line. UDCA derivatives induced GR translocation in a time dependent manner with equal efficacy to that of dexamethasone (Dex) and with greatly increased potency relative to UDCA. The cyclopropylamide 1a suppressed TNF-α induced NF-κB activity and it induced GRE transactivation. 1a was unable to displace Dex from the GR ligand binding domain (LBD) in a competition experiment but was capable of coactivator recruitment in a time-resolved fluorescence energy transfer assay (TR-FRET). This represents a novel mechanism of action for a GR modulator. These derivatives could result in a new class of GR modulators.

Original languageEnglish (US)
Pages (from-to)122-130
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Jan 13 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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