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

• Published in: The Journal of pharmacology and experimental therapeutics 2005-05, Vol.313 (2), p.492-501
• Main Authors: Kunsch, Charles, Luchoomun, Jayraz, Chen, Xi-Lin, Dodd, Geraldine L, Karu, Kanika S, Meng, Charles Q, Marino, Elaine M, Olliff, Lyn K, Piper, J Daniel, Qiu, Fei-Hua, Sikorski, James A, Somers, Patricia K, Suen, Ki-Ling, Thomas, Suzanne, Whalen, Anne M, Wasserman, Martin A, Sundell, Cynthia L
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidants - therapeutic use; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Cell Adhesion - drug effects; Cell Adhesion - physiology; Cells, Cultured; Cytokines - antagonists & inhibitors; Cytokines - secretion; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Silencing - drug effects; Gene Silencing - physiology; Humans; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Lipopolysaccharides - pharmacology; Oxidation-Reduction - drug effects; Probucol - analogs & derivatives; Probucol - chemistry; Probucol - pharmacology; Probucol - therapeutic use; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Synovial Membrane - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.080804

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)-α-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-α, IL-1β, and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF-α-induced nuclear translocation of nuclear factor of the κ-enhancer in B cells (NF-κB), 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.