The accumulation of non-enzymatic advanced glycation endproducts (AGEs) in tissues and organs as a normal part of the aging process is accelerated by hyperglycemia. These AGEs provoke inflammatory, angiogenic and sclerotic cytokines that ultimately cause dysfunctional tissue pathology. AGEs also quench available nitric oxide, a potent vasodilator and are a potent stimulant for oxidative stress through generation of reactive oxidant species.
Many syndromes including heart failure and those associated with diabetic complications such as erectile dysfunction, nephropathy, retinopathy, and atherosclerosis are associated with increased levels of these long-lived tissue modifications. These abnormal crosslinks between carbohydrates and proteins render tissues less susceptible to normal turnover thus leading to enhanced tissue or organ stiffness and hypertrophy. As such, left ventricular stiffness associated with diastolic dysfunction leads to abnormal filling times and pressures cascading to heart failure.
Inhibiting the formation of AGEs and AGE crosslinks or directly breaking AGE crosslinks offers the therapeutic possibility to reverse some of the pathologic deficits resulting from the accumulation of these abnormal structures. Alagebrium, formerly known as ALT-711, a AGE crosslink breaker (4,5-Dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride) has demonstrated the ability to reverse diabetic induced ED in rats, reduce left ventricular hypertrophy in models of diastolic heart failure, reduce pulse pressure in syndromes of enhanced vascular stiffness, retard the progression of atherosclerosis in ApoE knockout mice, and reduce cellular and biochemical aspects of diabetic nephropathy.
The use of alagebrium in human clinical trials has demonstrated a remarkable safety profile for the compound. Alagebrium the only AGE Crosslink Breaker in advanced human testing, has shown promising results in several Phase 2 trials and is being developed for cardiovascular indications such as heart failure with preserved ejection fraction, erectile dysfunction and diabetic nephropathy. Preliminary human studies have indicated that alagebrium is capable of improving endothelial dysfunction, a hallmark of cardiovascular disease and erectile dysfunction thus indicating the potential to modify attributes of impaired vasoreactivity.