COMPOUNDS AND METHODS FOR THERAPEUTIC INTERVENTION IN PREVENTING DIABETIC COMPLICATIONS

摘要

The present invention is based on the discovery of a metabolic pathway in which a specific kinase converts fructose-lysine into fructose-lysine-3-phosphate in an ATP dependent reaction. Fructose-lysine-3-phosphate (FL3P) is then broken down to form free lysine, inorganic phosphate and 3-deoxyglucosone (3DG), the latter being a reactive protein modifying agent. 3DG can be detoxified by reduction to 3-deoxyfructose (3DF), or it can react with endogenous proteins to form advanced glycation end-product modified proteins (AGE-proteins), which are believed to be a cause of diabetic complications. Disclosed is a class of compounds which inhibit the action of FL3P kinase in the above-mentioned pathway. Also disclosed are therapeutic methods of using such inhibitors to reduce formation of AGE-proteins and thereby lessen, reduce and delay diabetic complications, as well as methods for assessing a diabetic's risk of developing complications and for determining the efficacy of the disclosed inhibitor therapy by measuring the ratio of 3DG to 3DF in a biological sample following an oral dose of a fructose-lysine-containing food product.