BIOMAT Database Logo BIOMAT Database Logo

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. 2005

Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Department of Discovery Research, AtheroGenics, Inc., Alpharetta, GA 30004, USA. ckunsch@atherogenics.com

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.

UI MeSH Term Description Entries
D008070 Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: LIPID A, core polysaccharide, and O-specific chains (O ANTIGENS). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal B-cell mitogens commonly used in laboratory immunology. (From Dorland, 28th ed) Lipopolysaccharide,Lipoglycans
D010084 Oxidation-Reduction A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). Redox,Oxidation Reduction
D011341 Probucol A drug used to lower LDL and HDL cholesterol yet has little effect on serum-triglyceride or VLDL cholesterol. (From Martindale, The Extra Pharmacopoeia, 30th ed, p993). Biphenabid,DH-581,Lorelco,Lurselle,Panavir,Superlipid,DH 581,DH581
D002448 Cell Adhesion Adherence of cells to surfaces or to other cells. Adhesion, Cell,Adhesions, Cell,Cell Adhesions
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004730 Endothelium, Vascular Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components. Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000894 Anti-Inflammatory Agents, Non-Steroidal Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. Analgesics, Anti-Inflammatory,Aspirin-Like Agent,Aspirin-Like Agents,NSAID,Non-Steroidal Anti-Inflammatory Agent,Non-Steroidal Anti-Inflammatory Agents,Nonsteroidal Anti-Inflammatory Agent,Anti Inflammatory Agents, Nonsteroidal,Antiinflammatory Agents, Non Steroidal,Antiinflammatory Agents, Nonsteroidal,NSAIDs,Nonsteroidal Anti-Inflammatory Agents,Agent, Aspirin-Like,Agent, Non-Steroidal Anti-Inflammatory,Agent, Nonsteroidal Anti-Inflammatory,Anti-Inflammatory Agent, Non-Steroidal,Anti-Inflammatory Agent, Nonsteroidal,Anti-Inflammatory Analgesics,Aspirin Like Agent,Aspirin Like Agents,Non Steroidal Anti Inflammatory Agent,Non Steroidal Anti Inflammatory Agents,Nonsteroidal Anti Inflammatory Agent,Nonsteroidal Anti Inflammatory Agents,Nonsteroidal Antiinflammatory Agents
D000975 Antioxidants Naturally occurring or synthetic substances that inhibit or retard oxidation reactions. They counteract the damaging effects of oxidation in animal tissues. Anti-Oxidant,Antioxidant,Antioxidant Activity,Endogenous Antioxidant,Endogenous Antioxidants,Anti-Oxidant Effect,Anti-Oxidant Effects,Anti-Oxidants,Antioxidant Effect,Antioxidant Effects,Activity, Antioxidant,Anti Oxidant,Anti Oxidant Effect,Anti Oxidant Effects,Anti Oxidants,Antioxidant, Endogenous,Antioxidants, Endogenous

Related Publications

Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Anti-inflammatory activity of newly synthesized 2,6-bis-(1,1-dimethylethyl)phenol derivatives.
January 1993, Pharmacological research,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Hepatic microsomal induction profile of carbamic acid [[2,6-bis(1- methylethyl)phenoxy] sulfonyl]-2,6-bis(1-methylethyl) phenyl ester, monosodium salt (PD138142-15), a novel lipid regulating agent.
March 1995, Biochemical pharmacology,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Safety assessment of diethyl[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl] phosphonate for use in a food contact material.
March 2022, EFSA journal. European Food Safety Authority,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Synthesis and biological evaluation of 5-[[3,5-bis(1,1-dimethylethyl)- 4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and -imidazoles: novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity.
January 1994, Journal of medicinal chemistry,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
The pharmacologic effects of 5-[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, choline salt (CI-986), a novel inhibitor of arachidonic acid metabolism in models of inflammation, analgesia and gastric irritation.
January 1994, Prostaglandins,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Synthesis and hypolipidemic activity of novel 2-(4-(2-substituted aminothiazole-4-yl) phenoxy) acetic acid derivatives.
July 2010, European journal of medicinal chemistry,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acid.
December 2001, Bioorganic & medicinal chemistry,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
[Nonsteroidal anti-inflammatory agents. IV. Anti-inflammatory activity of alpha-[4-(1-tetralyl)-phenoxy]-isobutyric acid and alpha[4-(1-tetralyl)-phenylthio]-isobutyric acid].
November 1977, Bollettino chimico farmaceutico,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Synthesis and hypolipidemic activity of novel 2-(4-(2-amino-6-(4-substituted phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives.
April 2012, Chemical biology & drug design,
Charles Kunsch, and Jayraz Luchoomun, and Xi-Lin Chen, and Geraldine L Dodd, and Kanika S Karu, and Charles Q Meng, and Elaine M Marino, and Lyn K Olliff, and J Daniel Piper, and Fei-Hua Qiu, and James A Sikorski, and Patricia K Somers, and Ki-Ling Suen, and Suzanne Thomas, and Anne M Whalen, and Martin A Wasserman, and Cynthia L Sundell
Synthesis, structural characterization and DNA interaction of zinc complex from 2,6-diacetylpyridine dihydrazone and {4-[(2E)-2-(hydroxyimino)acetyl]phenoxy} acetic acid.
March 2015, Journal of photochemistry and photobiology. B, Biology,
Copied contents to your clipboard!