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AGI-1067: A Multifunctional Phenolic Antioxidant, Lipid Modulator, Anti-Inflammatory and Antiatherosclerotic Agent

2003; American Society for Pharmacology and Experimental Therapeutics; Volume: 305; Issue: 3 Linguagem: Inglês

10.1124/jpet.102.048132

1521-0103

Cynthia L. Sundell, Patricia K. Somers, Charles Q. Meng, Lee K. Hoong, Ki‐Ling Suen, Russell R. Hill, Laura K. Landers, Angela Chapman, Dustie N. Butteiger, Moira Jones, David G. Edwards, Alan Daugherty, Martin A. Wasserman, R. Wayne Alexander, Russell M. Medford, Uday Saxena,

Antioxidant Activity and Oxidative Stress

To explore the therapeutic efficacy and potential mechanisms of action of a new class of antiatherosclerotic drugs, AGI-1067 [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester] (butanedioc acid) was tested in several animal models of atherosclerosis. AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. In contrast, another phenolic antioxidant, probucol, had a modest LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). Histopathology of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis in LDL receptor-deficient (LDLr -/-) mice and apolipoprotein E-deficient (ApoE -/-) mice even in the absence of a lipid-lowering effect. In LDLr -/- mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE -/- mice, AGI-1067 reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited tumor necrosis factor-α-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC 50 values = 6, 10, and 25 μM, respectively). These data show that AGI-1067 can inhibit atherosclerosis not only via its lipid-lowering effects but also by having direct anti-inflammatory effects on the vessel wall and suggest that it may be a novel therapeutic agent for coronary artery disease.