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Despite significant advances in technology and technique, coronary restenosis remains the primary limitation of percutaneous transluminal coronary angioplasty (PTCA). Among patients undergoing PTCA, between 20% and 50% of patients who do not receive a stent and 10%-30% of those who do receive a stent develop restenosis within 6 months of the procedure. Drug-eluting stents, which release high local concentrations of antiproliferative or immunosuppressive agents directly into the vessel wall at the site of the lesion, have dramatically reduced the incidence of restenosis in patients undergoing PTCA. However, even with drug-eluting stents, a significant percentage of higher-risk patients develop in-stent restenosis. These data suggest that a role remains for effective, well-tolerated systemic pharmacologic therapies to further reduce the rate of restenosis. To date, the majority of systemic agents tested for restenosis prevention have failed to show significant benefit. Only 2 agents, probucol and cilostazol, have consistently demonstrated efficacy in preventing restenosis. In addition, the investigational agent AGI-1067 has demonstrated promising efficacy in early clinical trials. Together with drug-eluting stents, these therapies may for the first time reduce the rate of restenosis to near zero, even in high-risk patients, such as individuals with diabetes mellitus.

This review addresses the role of oxidative stress in the pathology of atherosclerosis and why it is now believed that atherosclerosis is not only a disease of oxidative stress but also of chronic inflammation. Perhaps more importantly, this review also describes the vascular protectant (V-protectant) technology platform originated at AtheroGenics, Inc., from which a series of inhibitory compounds has emerged to treat a number of chronic inflammatory diseases, including atherosclerosis. In atherosclerosis, these drugs not only act as antioxidants, but also as lipid modulators, inhibitors of inflammation, and inhibitors of gene expression. It is also important to understand the basis for considering vascular cell adhesion molecule-1 (VCAM-1) as a reduction-oxidation-sensitive protein, which has a key role in the early phases of atherosclerosis. The review concludes with a description of the design and chemistry of AtheroGenics' lead clinical development compound, AGI-1067, and an analysis of its preclinical in vitro and in vivo profile. AGI-1067 is a novel, potent antioxidant with anti-inflammatory properties. It inhibits gene expression of VCAM-1 and monocyte chemoattractant protein-1, decreases low-density lipoprotein cholesterol levels, and prevents atherosclerosis in a number of animal models. AGI-1067 is currently undergoing clinical trials as an antiatherosclerotic agent.

A large body of evidence points to oxidative stress as an important trigger in the complex chain of events leading to atherosclerosis. Reactive oxygen species have also been implicated in the pathophysiology of restenosis after percutaneous coronary interventions (PCI). The powerful antioxidant probucol has been shown to prevent coronary restenosis after balloon angioplasty in the MultiVitamins and Probucol (MVP) trial and other clinical studies. Probucol has also induced regression of carotid atherosclerosis in the Fukuoka Atherosclerosis Trial (FAST). However, prolongation of the QT interval with probucol remains a long-term safety concern. AGI-1067, a metabolically stable analog of probucol, is a vascular protectant (V-protectant) with strong antioxidant properties, equipotent to those of probucol. This V-protectant has been effective at preventing atherosclerosis in all tested animal models, including the low-density lipoprotein receptor-deficient and apolipoprotein E-knockout mice and the hypercholesterolemic primate. AGI-1067 improved luminal dimensions of the PCI site and reduced restenosis in the Canadian Antioxidant Restenosis Trial (CART-1). In contrast to probucol, AGI-1067 did not induce prolongation of the QT interval. AGI-1067 also improved luminal dimensions of the reference segments in the PCI vessels in CART-1, an effect that suggests a direct antiatherosclerosis effect. This has potentially important implications, as local approaches to prevent restenosis, such as coated stents, are not expected to prevent atherosclerosis progression, myocardial infarction, and cardiovascular death. Considering that oxidative stress and inflammation may persist for a prolonged period after stenting, treatment with AGI-1067 for the entire period of risk after PCI (instead of only 4 weeks in CART-1) may result in enhanced protection against luminal renarrowing in the ongoing multicenter CART-2 trial. Because the ultimate goal of therapy for patients with coronary artery disease must remain prevention of disease progression and atherosclerosis-related events, CART-2 will test the value of AGI-1067 for the reduction of both post-PCI restenosis and atherosclerosis progression.