title: AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid], a novel antioxidant and anti-inflammatory compound: cellular and biochemical characterization of antioxidant activity and inhibition of redox-sensitive inflammatory gene expression.
abstract: The pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis, is regulated, at least in part, by modulation of oxidation-reduction (redox) homeostasis and the expression of redox-sensitive inflammatory genes including adhesion molecules, chemokines, and cytokines. AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid] is a novel, orally active, phenolic antioxidant and anti-inflammatory compound with antirheumatic properties. To elucidate its anti-inflammatory mechanisms, we evaluated AGIX-4207 for a variety of cellular, biochemical, and molecular properties. AGIX-4207 exhibited potent antioxidant activity toward lipid peroxides in vitro and displayed enhanced cellular uptake relative to a structurally related drug, probucol. This resulted in potent inhibition of cellular levels of reactive oxygen species in multiple cell types. AGIX-4207 selectively inhibited tumor necrosis factor (TNF)-alpha-inducible levels of the redox-sensitive genes, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, with less inhibition of E-selectin, and no effect on intracellular adhesion molecule-1 expression in endothelial cells. In addition, AGIX-4207 inhibited cytokine-induced levels of monocyte chemoattractant protein-1, interleukin (IL)-6, and IL-8 from endothelial cells and human fibroblast-like synoviocytes as well as lipopolysaccharide-induced release of TNF-alpha, IL-1beta, and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF-alpha-induced nuclear translocation of nuclear factor of the kappa-enhancer in B cells (NF-kappaB), suggesting that the mechanism of action is independent of this redox-sensitive transcription factor. Taken together, these results provide a mechanistic framework for understanding the anti-inflammatory and antirheumatic activity of AGIX-4207 and provide further support for the view that inhibition of redox-sensitive inflammatory gene expression is an attractive approach for the treatment of chronic inflammatory diseases.
authors.affiliation: Department of Discovery Research, AtheroGenics, Inc., Alpharetta, GA 30004, USA. ckunsch@atherogenics.com
authors.forename: Charles
authors.initials: C
authors.lastname: Kunsch
authors.forename: Jayraz
authors.initials: J
authors.lastname: Luchoomun
authors.forename: Xi-Lin
authors.initials: XL
authors.lastname: Chen
authors.forename: Geraldine L
authors.initials: GL
authors.lastname: Dodd
authors.forename: Kanika S
authors.initials: KS
authors.lastname: Karu
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Meng
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Marino
authors.forename: Lyn K
authors.initials: LK
authors.lastname: Olliff
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Piper
authors.forename: Fei-Hua
authors.initials: FH
authors.lastname: Qiu
authors.forename: James A
authors.initials: JA
authors.lastname: Sikorski
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Somers
authors.forename: Ki-Ling
authors.initials: KL
authors.lastname: Suen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Thomas
authors.forename: Anne M
authors.initials: AM
authors.lastname: Whalen
authors.forename: Martin A
authors.initials: MA
authors.lastname: Wasserman
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sundell
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011341:Probucol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D018501:Antirheumatic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C494725:camobucol; D011341:Probucol