New aldose reductase inhibitors as potential agents for the prevention of long-term diabetic complications

The results of recent clinical trials emphasise the importance of an improved glycaemic control in diabetic patients in order to prevent or at least to delay long-term complications. The difficulty in obtaining normalisation of blood glucose values has underlined the importance of the search for new and effective aldose reductase inhibitors (ARIs) to control the consequences of elevated glucose levels, therefore delaying the onset and retarding the progression of diabetic complications such as neuropathy, nephropathy, retinopathy and cataract. Although the physiological role of aldose reductase (ALR2) has not been clearly elucidated yet, it has been shown that this enzyme, the first of the polyol pathway, is responsible for the production of sorbitol from glucose. There are several pieces of evidence which link this process to the occurrence of diabetic complications. Orally active aldose reductase inhibitors can be grouped into two chemical classes: cyclic imide and carboxylic acid derivatives. This review describes the recent insights into these two classes of inhibitors, and the further development of ARIs provided with antidiabetic and antihyperlipidaemic properties. The most recent developments in understanding of the structure, catalytic mechanism and biochemical behaviour of ALR2 are also reported.