title: The antagonists but not partial agonists of glucocorticoid receptor ligands show substantial side effect dissociation.
abstract: A synthetic glucocorticoid receptor (GR) ligand with the efficacy of a glucocorticoid, but without the accompanying side effects, would meet an unmet medical need for the treatment of inflammatory diseases. It was hypothesized that a GR ligand that shifted helix 12 in a manner distinct from an agonist and an antagonist would confer a distinct GR conformation, resulting in differential gene expression and, ultimately, dissociation of antiinflammatory activity from side effects. A structural feature expected to interfere with helix 12 was incorporated into a nonsteroidal, tricyclic scaffold to create novel, high-affinity, and selective GR ligands that manifested a dual function in cellular assays, partial but robust agonist activity for inflammatory cytokine inhibition, and full antagonist activity for reporter gene activation. In contrast, analogs not likely to hinder helix 12 exhibited partial agonist activity for reporter gene activation. The requirement of full antagonist activity for substantial side effect dissociation was demonstrated in primary human preadipocytes, hepatocytes, and osteoblasts in which effects on adipogenesis, key genes involved in gluconeogenesis, and genes important for bone formation were examined, respectively. The dissociated GR ligands, despite lacking significant reporter gene activation, weakly recruit a limited number of coactivators such as peroxisomal proliferator-activated receptor-γ coactivator 1α. Transcriptional activation was sensitive to both peroxisomal proliferator-activated receptor-γ coactivator 1α and GR levels, providing a basis for cell-selective modulation of gene expression. The antiinflammatory activity of the dissociated ligands was further demonstrated in mouse models of inflammation. Together these results suggest that these ligands are promising candidates with robust antiinflammatory activity and likely dissociation against glucocorticoid-induced side effects.
authors.affiliation: St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017, USA. sxhu2000@yahoo.com
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.forename: Sarah
authors.initials: S
authors.lastname: Du
authors.forename: Cansu
authors.initials: C
authors.lastname: Tunca
authors.forename: Timothy
authors.initials: T
authors.lastname: Braden
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Long
authors.forename: Jamie
authors.initials: J
authors.lastname: Lee
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Webb
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Dietz
authors.forename: Susan
authors.initials: S
authors.lastname: Hummert
authors.forename: Sharon
authors.initials: S
authors.lastname: Rouw
authors.forename: Shridhar G
authors.initials: SG
authors.lastname: Hegde
authors.forename: R Keith
authors.initials: RK
authors.lastname: Webber
authors.forename: Mark G
authors.initials: MG
authors.lastname: Obukowicz
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects*; D005943:Gluconeogenesis / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D015735:Mifepristone