title: Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators.
abstract: Ursodeoxycholic acid (UDCA) is used for the treatment of hepatic inflammatory diseases. Recent studies have shown that UDCA's 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland. rsharma@tcd.ie
authors.forename: Ruchika
authors.initials: R
authors.lastname: Sharma
authors.forename: David
authors.initials: D
authors.lastname: Prichard
authors.forename: Ferenc
authors.initials: F
authors.lastname: Majer
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Byrne
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
authors.forename: Aideen
authors.initials: A
authors.lastname: Long
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D004938:Esophageal Neoplasms; D031541:Fluorescence Resonance Energy Transfer; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D011869:Radioligand Assay; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000577:Amides; D005938:Glucocorticoids; D008024:Ligands; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D014580:Ursodeoxycholic Acid; D003907:Dexamethasone