The goal of this Phase I SBIR proposal is to demonstrate that inhibition of a novel kidney enzyme, fructosamine-3-kinase (Amadorase), that is responsible for the formation of 3-deoxyyglucosone (3DG), will reduce the formation of advanced glycation end products (AGEs) and therefore reduce diabetic retinopathy in STZ-induced diabetic rats. Amadorase phosphorylates fructoselysine, an Amadori product, to produce fructoselysine 3-phosphate (FL3P). FL3P is unstable and decomposes to lysine, inorganic phosphate, and 3-deoxyglucosone (3DG), a highly reactive dicarbonyl sugar. 3DG is a precursor to advanced glycation end products (AGEs), which play a role in the development of diabetic nephropathy, retinopathy, neuropathy, and heart disease. Since Amadorase is responsible for most of the in vivo production of 3DG, it is an exciting new potential therapeutic target for diabetic complications. There are presently no treatments to halt the progression of diabetic complications, therefore any level of reduction obtained is extremely important to the health and well being of diabetics. To perform these studies, Dynamis will use its lead compound, DYN 12 (3-o-methysorbitollysine), which lowers systemic 3DG levels in rats. Reduction of indications of retinopathy for diabetic rats on and off DYN 12 will allow Dynamis to proceed to pre-clinical trials in vertebrates. Acute and chronic toxicology, stability, formulation, analytical methods and, pharmacology studies with DYN 12 will be performed with the intent of filing an IND.
Thesaurus Terms: alcohol phosphotransferase, deoxyglucose, diabetic retinopathy, drug design /synthesis /production, drug screening /evaluation, eye agent adduct, glycation, imidazole, nitric oxide synthase electroretinography, laboratory rat
