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Alagebrium (formerly known as ALT-711; chemical name 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride) is a drug produced by Synvista Therapeutics Inc., which is currently being evaluated in clinical trials. It is the first drug to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (A.G.E.s), thereby reversing one of the main mechanisms of aging. Through this effect alagebrium is designed to increase cardiac and vascular compliance cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking, such as diabetic nephropathy, a form of kidney disease.
A.G.E.s are permanent carbohydrate structures that form when carbohydrates bind to proteins, lipids and DNA. Many proteins, including structural proteins such as collagen and elastin, play an integral role in the architecture of tissues and organs and maintenance of cardiovascular elasticity and vascular wall integrity. Diabetic individuals form excessive amounts of A.G.E.s earlier in life than non-diabetic individuals. This process can impair the normal function of organs that depend on flexibility for normal function, such as blood vessels and cardiac muscle. The formation of A.G.E. crosslinks leads to increased stiffness and loss of function of tissues and organs, and abnormal protein accumulation, which together cause many of the complications of aging and diabetes. A.G.E.s are also known to induce oxidative stress, in which reactive molecules provoke the underlying component of inflammation.
Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to the stiffness of the cardiovascular system. Removal of the A.G.E.s by cleavage of the abnormal crosslinking bonds has been associated with diminished inflammatory and sclerotic signaling pathways. These pathways are responsible for the deposition of abnormal amounts of matrix proteins that physically stiffen tissues. The presence of A.G.E. crosslinks also renders tissues and organs less susceptible to normal turnover thus enhancing the presence of these abnormal bonds on various molecules. Importantly, alagebrium does not disrupt the natural carbohydrate modification to proteins, intra-molecular crosslinking or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function is preserved while abnormal crosslinking is reduced.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Alagebrium". A list of authors is available in Wikipedia.|