Advanced Glycation End-Product Cross-Link Breakers
Overview
Isolated systolic hypertension (isolated systolic hypertension) accounts for approximately 65% of the overall incidence of uncontrolled hypertension in the United States and is particularly prevalent in the elderly. Furthermore, systolic hypertension may be resistant to currently available antihypertensive agents.
Systolic hypertension is associated with age-related changes in arterial function, mainly a loss of arterial compliance and a corresponding increase in arterial stiffness. These factors have been correlated with coronary artery disease. Stiffness of the myocardium also increases with age and may lead to diastolic dysfunction.
The decline in arterial and myocardial compliance is a direct result of changes in the collagen composition of blood vessels and the heart, as well as an increase in collagen mass; it is characterized by an increase in collagen cross-linking. One of the major contributors to increasing arterial and myocardial stiffness is the formation of advanced glycation end products (AGEs). AGEs begin as reversible products formed by the nonenzymatic interaction between reducing sugars (such as glucose) and proteins but eventually lead to the formation of carbonyl (C = O) bonds, which can form permanent cross-links between adjacent protein molecules. These AGEs not only impair vessel function but may also inhibit cellular transport, stimulate pro-inflammatory responses, and contribute to endothelial dysfunction.
Attention has focused on drugs that inhibit or reverse this cross-linking process. One compound that targets AGE cross-links is BioStratum’s pyridoxamine (Pyridorin), which is in Phase II development for diabetic nephropathy but is not under development for hypertension.
Mechanism Of Action
One of the major contributors to collagen cross-linking is the formation of AGEs. AGEs begin as reversible, noncovalent associations between reducing sugars and proteins, but through a series of reactions, they become stable cross-links.
AGE cross-link inhibitors prevent the formation of stable protein-protein bonds by interacting with carbonyl intermediaries. AGE cross-link breakers, such as those based on thiazolium derivatives, interact with carbonyl moieties between cross-linked protein molecules to break the protein-protein bond.
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