New oral antiinflammatory antioxidants

AGI-1067 (succinobucol 44, Figure 15), a metabolically stable derivative of probucol, where the introduction of a monosuccinate ester group alters its overall in vitro and in vivo pharmacology, is a new oral antioxidant being tested in atherosclerosis. AGI-1067, like probucol, is a potent extracellular antioxidant but has an enhanced intracellular uptake capability compared to probucol. AGI-1067 inhibited intracellular ROS production whereas probucol had no effect and also inhibited proinflammatory gene expression in stimulated endothelial cells, including the expression of several proteins associated with atherosclerosis: VCAM-1 and MCP-1.93 In LPS-challenged mice, oral dosing with AGI-1067 reduced VCAM-1 and MCP-1 mRNA levels. In LDLr "7" mice, AGI-1067 reduced aortic atherosclerosis by 49% in the absence of a lipid-lowering effect.94 Like probucol, oral dosing with AGI-1067 inhibited restenosis in phase II trials, but an important antiatherosclerotic effect was observed in the nonintervened arterial segments. This effect was not observed with probucol. The observed reductions in atheroma volume were sufficiently robust for AGI-1067 to enter phase III testing in a secondary prevention trial targeting atherosclerosis in 2004. If successful, this trial should demonstrate the potential benefit of novel antioxidant-based anti-inflammatory agents as potential new therapies for CHD patients.95,96

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