Pharmacological approaches to the treatment of diabetic complications

Abstract

Diabetes is often accompanied by several long-term complications such as neuropathy, nephropathy, retinopathy, cataract and angiopathy; their occurrence has been linked to the modification of the physiological levels of glycaemia. Several interrelated metabolic pathways have been implicated in the toxic effects of glucose; the polyol pathways was one of the first considered. However, while in diabetic animal models the inhibitors of aldose reductase (ALR2, the first enzyme of this pathway) seem to be active, 16 years of clinical trials, based mainly on neuropathy, have been inconclusive; only one drug currently being marketed. Newer potent and selective aldose reductase inhibitors have been discovered in the last few years, but the lack of commercial success has probably led to the very rapid decrease in the number of patents relating to newer aldose reductase inhibitors. Inhibition of the second enzyme of this pathway, sorbitol dehydrogenase (SDH), has been shown to be detrimental. Other approaches for the prevention and the delay of progression of diabetic complications seem to be more promising, namely, the inhibition of the formation of advanced glycated end products (AGEs) or protein kinase C (PKC) β2 inhibition; compounds acting on these two pathways have proved effective in retarding the development of diabetic complications in animal models and some products are in clinical trials at the moment. Renewed attention has been paid to vascular involvement in the pathogenesis of diabetic neuropathy; the biological activity of C-peptide and the role of endothelin-1 (ET-1) in diabetic vascular disease are emerging as a new research area for the treatment of diabetic complications

Synthesis and Evaluation of Some New 2-(5-(4-Benzamidobenzylidene)-2,4dioxothiazolidin-3-Yl)acetic Acid Analogs as Aldose Reductase Inhibitors

“…A variety of ARIs have been reported; however, in clinical studies, many of them have exhibited low efficacy or a narrow spectrum of tissue activity, generally because of unfavorable pharmacokinetics, or have proved to produce toxic side-effects. At present, epalrestat is the only ARI available on the market [10][11][12]. Literature reveals that in the last few years, numerous 5-arylidene-2,4-thiazolidinediones derivatives produced appreciable ALR inhibition [13,14], but their effectiveness generally decreases in vivo, probably due to their poor penetrability to key target tissues, in particular, peripheral nerves [15][16][17].…”

A new approach for the synthesis of bioactive heteroaryl thiazolidine-2,4-diones

“…[3][4][5] Besides, it was reported that some 2,4-TZDs have been used as antihyperglycemic 6 and aldose reductase (AR) inhibitory agents with dual activity. 7 There is a great interest in 2,4-TZD derivatives as aldose reductase inhibitors (ARIs), 7,8 since they can be viewed as hydantoin bioisosters potentially free of the hypersensitivity reactions which are linked to the presence of the hydantoin system.…”

Exploration of QSAR modelling techniques and their combination to rationalize the physicochemical characters of nitrophenyl derivatives towards aldose reductase inhibition

“…Over the last three decades numerous ALR2 inhibitors (ARIs) have been identified, most of which belong to the carboxylic acids (such as zopolrestat, ponalrestat, epalrestat) and hydantoins (such as sorbinil) classes of compounds. [1][2][3][4][8][9][10][11] Nevertheless, many of them have shown to be clinically inadequate because of adverse pharmacokinetics or toxic side-effects. [10] At present, epalrestat is the only ARI available on the market.…”