Experimental and clinical studies show that the probucol derivative AGI-1067 prevents vascular growth.

Abstract

AGI-1067 is a derivative of probucol that is a promising new development for the treatment of restenosis and possibly atherosclerosis. In monkeys fed a high-fat diet for 1 year, AGI-1067 prevented the development of atherosclerosis. In these monkeys, AGI-1067 lowered plasma levels of low-density lipoprotein (LDL)-cholesterol and, in contrast to probucol, was capable of increasing high-density lipoprotein (HDL)-cholesterol levels. Although AGI1067 did not have marked lipid-lowering effects in two transgenic mouse models (the LDL-receptor-deficient and apolipoprotein-E-deficient models) fed a high-fat chow, it decreased the atherosclerotic lesion area in the aorta. In a mouse model of acute inflammation, the mRNA for the pro-inflammatory vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 was upregulated and this was inhibited by AGI-1067. AGI-1067 inhibited the TNF-alpha induction of redox-sensitive inflammatory proteins, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 and Eselectin, in cell culture. In addition, AGI-1067 is an antioxidant. In the Canadian Antioxidant Restenosis Trial (CART-1) of AGI-1067 in percutaneous coronary interventions, AGI-1067 had no effect on LDL-cholesterol but lowered HDL-cholesterol. At 6 months follow up, the lumen area of the percutaneous coronary interventions segments was greater in patients treated with AGI1067 than in untreated patients. Restenosis rates were 37.5% in the placebo group and 26% in the AGI-1067 group. The lumen area of reference segments was reduced in the placebo group but increased with the higher doses of AGI1067. Unlike probucol, AGI-1067 did not alter QTc interval.

• Authors: Sheila A Doggrell
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 12 Issue 11 Pg. 1855-9 (Nov 2003) ISSN: 1354-3784 [Print] England
• PMID: 14585060 (Publication Type: Comparative Study, Journal Article, Review)

Chemical References

• Anticholesteremic Agents
• Antioxidants
• succinobucol
• Probucol

Topics

• Animals
• Anticholesteremic Agents (therapeutic use)
• Antioxidants (therapeutic use)
• Arteriosclerosis (drug therapy, pathology)
• Clinical Trials as Topic
• Coronary Restenosis (drug therapy)
• Disease Models, Animal
• Endothelium, Vascular (drug effects, pathology)
• Humans
• Probucol (analogs & derivatives, therapeutic use)