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
Evidence of Promising Preclinical Results
The available literature indicates that ALT-711 showed promising results in animals before human trials began. These experimental and preclinical studies demonstrated that the drug could improve cardiac function and reduce symptoms in heart failure models. The fact that researchers proceeded from animal studies to human clinical trials suggests that the preclinical safety and efficacy data were sufficiently encouraging to warrant further investigation.
Mechanism Validation in Animal Models
Animal studies focused on validating the proposed mechanism of action—that breaking AGE cross-links would actually restore tissue flexibility and improve organ function.
My group did an extensive study into the mechanism of action of ALT-711, in which we evaluated the effects of treatment with ALT-711 on functional arterial wall properties in diabetic rats. This work was done in the department of Professor Bernard Levy in Paris. Male Wistar rats were made diabetic at the age of 9–10 weeks by i.p. injection of 70 mg/kg of streptozotocin. Only animals that developed blood glucose levels >15 mmol/liter were used. After 9 weeks of diabetes, the animals were divided into three groups: one group was studied to assess the exact hemodynamic changes that were caused by the diabetic state (n = 13), and two groups received ALT-711 (1.0 mg/kg per day i.p.) for either 1 or 3 weeks (n = 8–10 animals in each group) to assess possible reversal of the diabetes-induced cardiovascular abnormalities by treatment with this compound.
The different approaches used in these studies consistently show the beneficial effects of treatment with the AGE breaker ALT-711 on arterial elasticity. In vivo, treatment increased systemic arterial compliance (SAC) and reduced characteristic aortic input impedance (Zc). There was a decrease in carotid artery stiffness, as assessed with ultrasound in vivo and in vitro. These effects seemed to be related to the duration of the treatment, with stronger effects after 3 weeks than after 1 week. The finding of the marked increase in compliance and decrease in impedance cannot be attributed to differences in BP, which did not change during treatment; therefore, it reflects intrinsic modifications of the mechanical properties of the arterial wall. The increase of SAC and decrease of Zc indicate that because of treatment with ALT-711 the stiffness of the aorta was reduced by 25% (SAC) to 35% (Zc) to levels comparable to those observed in nondiabetic animals. This improvement was comparable to our results achieved with preventive treatment with aminoguanidine in diabetic rats.
In healthy older monkeys without diabetes, ALT-711 improved both arterial and ventricular function and optimised ventriculo-vascular coupling (https://pubmed.ncbi.nlm.nih.gov/11158613/).
In aged dogs, 1 month of administration of ALT-711 yielded a significant reduction (approximately 40%) in age-related left ventricular (LV) stiffness. This decrease was accompanied by an improvement in cardiac function (https://pubmed.ncbi.nlm.nih.gov/10706607/). Furthermore, in Sprague-Dawley rats made diabetic with a streptozotocin injection, ALT-711 treatment restored LV collagen solubility and cardiac BNP, in association with reduced cardiac AGE levels and abrogation of the increases in RAGE, AGE-R3, CTGF, and collagen III expression (https://pubmed.ncbi.nlm.nih.gov/12623881/). And a study in dogs confirmed these beneficial effects on the heart. Diabetes induced in the aging heart decreased LV systolic function (LV ejection fraction fell by 25%), increased aortic stiffness, and increased collagen type I and type III protein content. ALT-711 restored LV ejection fraction, reduced aortic stiffness and LV mass with no reduction in blood glucose level, and reversed the upregulation of collagen type I and type III. Myocardial LV collagen solubility (%) increased significantly after treatment with ALT-711 (https://pubmed.ncbi.nlm.nih.gov/12946933/).
Part 3: Clinical Studies in Humans
will follow soon
Prepared with assistance by Perplexity.
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