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

Abstract

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 Ϫ/Ϫ) mice and apolipoprotein E-deficient (ApoE Ϫ/Ϫ) mice even in the absence of a lipid-lowering effect. In LDLr Ϫ/Ϫ mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE Ϫ/Ϫ 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 50 values ϭ 6, 10, and 25 M, 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.

An investigation of the antiplatelet effects of succinobucol (AGI-1067)

“…Doses of succinobucol up to 150 mg/kg had no effect on MAP or HR in anaesthetized rats. These doses are in line with previous in vivo studies in animals [2], albeit that treatment was chronic in this study. A previous study reported raised systolic blood pressure in humans taking succinobucol chronically [5] but we observed no effect after acute administration in rats, suggesting that effects on blood pressure develop over time.…”

“…Succinobucol [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) is a phenolic antioxidant derivative of probucol, which has consistently demonstrated improved pharmacokinetics, antiproliferative, and anti-inflammatory effects compared with probucol [1][2][3]. Succinobucol inhibits cytokine release by monocytes and expression of proinflammatory cell adhesion molecules by endothelial cells (ECs) [4].…”

The LDL modification hypothesis of atherogenesis: an update

“…The drug (AGI-1067) had been shown to inhibit atherogenesis in animal models (42), but it failed to show any decrease in its primary composite end point of cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization above that seen with statin therapy alone (43). Data to evaluate antioxidant effect were not presented.…”

Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE−/− mice

“…Furthermore, these peptides do not appear to significantly alter plasma lipid parameters. In this respect, synthetic small molecule ACAT inhibitors have also been shown to have this effect without reducing plasma cholesterol levels (26)(27)(28). This is not surprising, because the administration of these peptides, as liposomes, would target M primarily and not the total body synthesis of cholesterol.…”