ABSTRACT
Atherosclerosis is a disease of oxidative stress and inflammation. AGI-1067 [butanedioic acid, mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-,hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis (1,1-dimethylethyl)phenyl] ester] is a metabolically stable derivative of, yet pharmacologically distinct from, the antioxidant drug probucol. It is a member of a novel class of orally active, antioxidant, anti-inflammatory compounds termed vascular protectants and exhibits antiatherosclerotic properties in multiple animal models and in humans. To elucidate its antiatherosclerotic mechanisms, we have evaluated several cellular and molecular properties of AGI-1067 in vitro. AGI-1067 exhibited potent lipid peroxide antioxidant activity comparable with probucol yet demonstrated significantly enhanced cellular uptake over that observed with probucol. AGI-1067, but not probucol, inhibited basal levels of reactive oxygen species (ROS) in cultured primary human endothelial cells and both basal and hydrogen peroxide-induced levels of ROS in the promonocytic cell line, U937. Furthermore, AGI-1067 inhibited the inducible expression of the redox-sensitive genes, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1, in endothelial cells as well as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 production in peripheral blood mononuclear cells, whereas probucol had no effect. cDNA array hybridization experiments demonstrated that AGI-1067 selectively inhibited the expression of only a subset of TNF-alpha-responsive and nuclear factor-kappaB (NF-kappaB)-inducible genes in endothelial cells. The inhibitory effect of AGI-1067 on inducible VCAM-1 gene expression occurred at the transcriptional level, yet AGI-1067 had no effect on the activation of the redox-sensitive transcription factor NF-kappaB. These studies suggest that the anti-inflammatory and antiatherosclerotic properties of AGI-1067 may be due to selective inhibition of redox-sensitive endothelial and monocyte inflammatory gene expression. These studies provide a molecular basis for understanding the mechanism of action of this new class of therapeutic antiatherosclerotic compounds.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Endothelium, Vascular/drug effects , Monocytes/drug effects , Probucol/analogs & derivatives , Probucol/pharmacology , Active Transport, Cell Nucleus/drug effects , Aorta , Cells, Cultured , Cytokines/metabolism , Drug Interactions , Endothelium, Vascular/metabolism , Gene Expression/drug effects , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , NF-kappa B/metabolism , Oxidation-Reduction/drug effects , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
A series of novel phenolic compounds has been discovered as potent inhibitors of TNF-alpha-inducible expression of vascular cell adhesion molecule-1 (VCAM-1) with concurrent antioxidant and lipid-modulating properties. Optimization of these multifunctional agents led to the identification of 3a (AGI-1067) as a clinical candidate with demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia.
