Abstract:Diabetic complications including nephropathy, neuropathy and cataract are the leading causes of end stage renal diseases and neurological disorders, respectively. The annual cost for patients with diabetes-related renal diseases and neurological disorder exceeds several billion dollars. Recent epidemiologic studies suggest that genetic factors play an important role in the pathogenesis of diabetic complications. Indeed, diabetes increases the incidence of cardiovascular disease as well as the complications of myocardial infarction. Studies using animal models of diabetes have demonstrated that the metabolic alterations occurring at the myocyte level may contribute to the severity of ischemic injury in diabetic hearts.
It is well-known that the polyol pathway has been concerned in the etiology of complications of diabetes. Aldose reductase (AR), the rate limiting enzyme of the polyol pathway, catalyses the reduction of glucose to sorbitol using NADPH as a cofactor, is responsible most of the diabetic complications and is broadly distributed in several tissues. AR consists of a single polypeptide chain consisting of 315 residues and several crystal structures of the enzyme have been solved by X-ray crystallography. It is now obvious that the genetically modified AR gene resulted polymorphism association with various metabolic and environmental factors, is responsible in the modulation of the risk related to diabetic complications. Therefore, identification of the polymorphism related to gene differentiation is becoming one of the major areas in the treatment of diabetic complications. Although it is needed some progress in the human genome project as well as advances in the gene therapy, still tradiational structure-based and / or ligand-based drug design methods have become more important as a rational approach to the finding of novel AR inhibitors (ARIs) for remedy of such complications. Inhibition of AR affords a therapeutically rational resources to slow down the onset or development of such diabetic complications. An important goal for new ARIs is hence improvement of the tolerability and the treatment in the areas mentioned above.
ARIs (both from nature and synthetic) block the flux of glucose through the polyol pathway and prevent or reverse functional deficits and structural damage in the lens, retina, kidney, and peripheral nerves. A variety of structurally diverse compounds have been observed to inhibit AR. Although several of these compounds have progressed to the clinical level, very few such drugs are currently being considered for the market.
The quest for useful, orally active ARIs has been underway for more than three decades, indeed, after almost 20 years of clinical trials on certain diabetic complications, still there is no optimized compound for the effective treatment. Clinical studies appear to be limited to slowing the progression of certain diabetic complications rather than to its reversal. Several reasons could be attributed to the lack of convincing effectiveness for ARIs but it is thought that the future trends for the treatment of diabetic complications could be aided by the integration of the recent progresses in the application of generelated strategies to therapy, and the consideration of the availability for the precise interactions of the novel ARIs on specific genes.
Document Type: Book Review
Affiliations: Ankara University Faculty of Pharmacy (ECZACILIK) Department of Pharmaceutical Chemistry Tandogan 06100, Ankara Turkey.
Publication date: August 1, 2003
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