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CARDIOVASCULAR
AtheroGenics, Inc., Alpharetta, Georgia (C.L.S., P.K.S., C.Q.M., L.K.H., K.-L.S., R.R.H., L.K.L., A.C., D.E., M.A.W., R.M.M., U.S.); University of Kentucky, Lexington, Kentucky (D.B., A.D.); Quintiles, Ltd, Edinburgh, Scotland, United Kingdom (M.J.); and Emory University School of Medicine, Atlanta, Georgia (R.W.A.)
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-
-inducible expression of VCAM-1, MCP-1, and
E-selectin in human aortic endothelial cells (IC 50values = 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.
Address correspondence to: Dr. Cynthia L. Sundell, Discovery Research, AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, GA 30004. E-mail: csundell{at}atherogenics.com
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