Chemistry and pharmacology of vascular protectants: a novel approach to the treatment of atherosclerosis and coronary artery disease.
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.
Wasserman
Martin A
MA
Department of Discovery Research, AtheroGenics, Inc., Alpharetta, Georgia 30004, USA. mwasserman@atherogenics.com
Sundell
Cynthia L
CL
Kunsch
Charles
C
Edwards
David
D
Meng
Charles Q
CQ
Medford
Russell M
RM
D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002319:Cardiovascular System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D011341:Probucol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; C471047:succinobucol; D011341:Probucol