Targeting advanced glycation with pharmaceutical agents: where are we now?

Abstract

Advanced glycation end products (AGEs) are the final products of the Maillard reaction, a complex process that has been studied by food chemists for a century. Over the past 30 years, the biological significance of advanced glycation has also been discovered. There is mounting evidence that advanced glycation plays a homeostatic role within the body and that food-related Maillard products, intermediates such as reactive α-dicarbonyl compounds and AGEs, may influence this process. It remains to be understood, at what point AGEs and their intermediates become pathogenic and contribute to the pathogenesis of chronic diseases that inflict current society. Diabetes and its complications have been a major focus of AGE biology due to the abundance of excess sugar and α-dicarbonyls in this family of diseases. While further temporal information is required, a number of pharmacological agents that inhibit components of the advanced glycation pathway have already showed promising results in preclinical models. These therapies appear to have a wide range of mechanistic actions to reduce AGE load. Some of these agents including Alagebrium, have translated successfully to clinical trials, while others such as aminoguanidine, have had undesirable side-effect profiles. This review will discuss different pharmacological agents that have been used to reduce AGE burden in preclinical models of disease with a focus on diabetes and its complications, compare outcomes of those therapies that have reached clinical trials, and provide further rationale for the use of inhibitors of the glycation pathway in chronic diseases.

Dicarbonyls and Advanced Glycation End-Products in the Development of Diabetic Complications and Targets for Intervention

“…Scavengers were the first drugs to be developed and tested in clinical trials to target the elevated dicarbonyl levels and results have been reviewed in [135]. Aminoguanidine was the prototype AGE inhibitor [136].…”

“…Positive effects were also seen on diabetic nephropathy in rats [166]. As opposed to pyridoxamine, clinical trials for alagebrium in diabetic and non-diabetic patients focused on macrovascular and cardiac related parameters such as blood pressure, left ventricular ejection fraction, left ventricular stiffness, endothelial function and arterial function [135]. While some clinical trials showed modest improvements, others were negative and currently no further trials are running.…”

“…In pre-clinical trials drugs were often given at high doses with aminoguanidine and pyridoxamine administered at up to 1 g/kg/day in rats [139,148,150]. Doses of pyridoxamine and aminoguanidine in clinical trials were much lower at 100–500 mg/day (1.4–7.1 mg/kg/day at 70 kg body weight) and 100–600 mg/day (1.4–8.6 mg/kg/day) respectively, even though allometric scaling needs to be considered [135,177]. It is thus possible that doses were too low to result in a therapeutic effect.…”

“…It is thus possible that doses were too low to result in a therapeutic effect. Moreover, as mentioned by Borg and Forbes, it is possible that targeting one pathway of AGE formation is not enough [135]. Treatment with dicarbonyl scavengers and GLO1 inducers does not prevent the transition metal catalyzed fragmentation of glucose and glucose lysine adducts and formation of associated AGEs.…”

“…AGE breakers were designed based on the idea that a compound must cleave previously formed AGEs to treat complications associated with elevated AGE levels [135]. This is not necessarily the case, as AGE modified proteins are cleared via protein turnover.…”