Promising medication which did not ‘make it’…
Part 1: Chemistry and Mechanism of Action
Advanced Glycation End Products
ALT-711, also known as alagebrium, is a pharmaceutical compound designed to address a specific biological problem: the accumulation of so-called advanced glycation end products (AGEs) in the human body. To understand how this drug works, we first need to grasp what AGEs are and why they matter.
AGEs form naturally in our bodies through a chemical process called glycation. When glucose molecules are present in our body at high levels -for instance, in people with diabetes or during normal ageing – they bond with or attach to proteins and other molecules in our tissues. These sugar-protein bonds are essentially permanent connections that stiffen and damage the structures they attach to. Some of these bonds are cross-linking bonds: the glucose bond allows two proteins to attach to each other, it acts as a sort of glue, making two protein molecules stick to each other. Over time, such AGEs accumulate in blood vessels, the heart, kidneys, and other organs, causing them to lose flexibility and function properly.
The Mechanism: Breaking Chemical Bonds
ALT-711 operates through a unique mechanism that sets it apart from other drugs. Rather than preventing new AGEs from forming (which other compounds like aminoguanidine attempt to do), ALT-711 actually breaks existing cross-links that have already formed between glucose and proteins. Think of it like untangling a knot that’s already been tied—it goes to work on damage that’s already done.
Specifically, ALT-711 cleaves carbohydrate-protein bonds that are characteristic of AGE complexes. This reversal of existing damage is groundbreaking because AGE cross-links were previously thought to be permanent. By breaking these bonds, ALT-711 can theoretically restore flexibility to stiffened tissues, particularly in blood vessels and the heart.
Why This Matters for Blood Vessels and the Heart
When AGEs accumulate in large arteries, they cause arteries to stiffen and lose their natural elasticity. Normally, arteries are flexible tubes that expand and contract with each heartbeat, helping to pump blood throughout the body. When AGEs cause stiffening, this natural pumping action becomes compromised. By breaking AGE cross-links, ALT-711 can restore large artery compliance—essentially returning flexibility and volume capacity to blood vessels. This improved elasticity means blood vessels can function more like they should, potentially reducing strain on the heart and improving overall cardiovascular function.
Chemical Classification
ALT-711 represents a first-of-its-kind class of drugs called AGE crosslink breakers. Unlike previous approaches that focused on slowing AGE formation, this compound targets the fundamental structural problem: the rigid bonds that make tissues stiff and dysfunctional.
The significance of this approach cannot be overstated. If successful, it would represent a therapeutic paradigm shift—moving from prevention to reversal in addressing ageing-related vascular stiffness and dysfunction.
References:
* Treskes M, Wolffenbuttel BHR. Lange termijn schade van diabetes mellitus: de rol van irreversibele glyceringsproducten. Ned Tijdschr Geneeskd 1996; 140: 1299-1303.
* Wolffenbuttel BHR, Boulanger CM, Crijns FRL, Huijberts MSP, Poitevin P, Swennen GNM, Vasan S, Egan JJ, Cerami A, Lévy BI. Breakers of advanced glycation endproducts restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA 1998; 4630-4.
* Mentink CJ, Hendriks M, Levels AA, Wolffenbuttel BHR. Glucose-mediated cross-linking of collagen in rat tendon and skin. Clin Chim Acta 2002; 321: 69-76.
Source for the figures:
* Mentink, C. Thesis AGEs and diabetic complications. Maastricht, 2006
* Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog. Horm. Res. 2001;56:1-21.
Part 2: Animal Studies
will follow soon
Prepared with assistance by Perplexity.
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