Alagebrium

Alagebrium

File:Alagebrium structure.svg
File:Alagebrium sf.gif
Systematic (IUPAC) name
4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride
Identifiers
CAS Number	341028-37-3
ATC code	none
PubChem	CID 216306
ChemSpider	187495
Chemical data
Formula	C13H14ClNOS
Molar mass	267.774 g/mol[[]]

Alagebrium (formerly known as ALT-711) is a failed drug candidate developed by Alteon Corporation. It was 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 reverse the stiffening of blood vessel walls that contributes to hypertension and cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking. Alagebrium has proven effective in reducing systolic blood pressure and providing therapeutic benefit for patients with diastolic heart failure.

Mechanism

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.

Although alagebrium may break some important A.G.E. crosslinks, there is no evidence that it is effective against the most prevalent crosslink: glucosepane.

History

The chemical compound had been discovered many years ago, and had traveled a circuitous route through academia, research firms, and finally, Alteon. There are two prominent attributes to Alagebrium (as Alteon renamed it). The first is that it is not a difficult compound to synthesize. An active black market rose very quickly after the early Phase I and II tests came in. Independent, lab-tested, certified for purity product was available for a short time on the grey market at about $3 per gram.

Although Alagebrium has shown very promising Phase I and II clinical trials, active research stopped because Alteon had run out of operating cash. Alteon, having a huge amount of convertible preferred stock hanging over its head (held by Genentech), had increasing difficulty raising subsequent levels of venture capital until finally, it was unavailable at any price. On 25 July 2007 Alteon was bought by a three-man operation developing another medication. The company changed its name to Synvista Therapeutics, Inc.

See also

• Glycation
• Glycosylation
• Glucosepane
• Advanced glycation end product