Alagebrium
Encyclopedia
Alagebrium 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 endproduct
s (AGEs), 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.
Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to the stiffness of the cardiovascular system. Removal of the AGEs 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 AGE 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 AGE crosslinks, there is no evidence that it is effective against the most prevalent crosslink: glucosepane
.
Although Alagebrium has shown very promising Phase I and II clinical trial
s, 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, and announced that it was terminating clinical trials in January of 2009. The company seems to have discontinued operations and their website is no longer available.
Advanced glycation endproduct
An advanced glycation end-product is the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. An advanced glycation...
s (AGEs), 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
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, as well as many other forms of degradation associated with protein crosslinking. Alagebrium has proven effective in reducing systolic
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
and providing therapeutic benefit for patients with diastolic
Diastole
Diastole is the period of time when the heart fills with blood after systole . Ventricular diastole is the period during which the ventricles are relaxing, while atrial diastole is the period during which the atria are relaxing...
heart failure.
Mechanism
AGEs 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 AGEs 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 AGE 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. AGEs 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 AGEs 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 AGE 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 AGE crosslinks, there is no evidence that it is effective against the most prevalent crosslink: glucosepane
Glucosepane
Glucosepane is a lysine-arginine protein cross-linking product and advanced glycation end product derived from D-glucose. It is an irreversible, covalent cross-link product that has been found to make intermolecular and intramolecular cross-links in the collagen of the extracellular matrix and...
.
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 arose very quickly after the early Phase I and II tests ended. 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 trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, 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, and announced that it was terminating clinical trials in January of 2009. The company seems to have discontinued operations and their website is no longer available.
See also
- GlycationGlycationGlycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
- GlycosylationGlycosylationGlycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
- GlucosepaneGlucosepaneGlucosepane is a lysine-arginine protein cross-linking product and advanced glycation end product derived from D-glucose. It is an irreversible, covalent cross-link product that has been found to make intermolecular and intramolecular cross-links in the collagen of the extracellular matrix and...
- Advanced glycation end product