Novel Inhibitors of Advanced Glycation Endproducts

Abstract

Enhanced formation and accumulation of advanced glycation endproducts (AGE's) have been proposed to play a major role in the pathogenesis of diabetic complications, aging, atherosclerosis, and Alzheimer disease leading to progressive and irreversible intermolecular protein crosslinkings. This process is accelerated in diabetes and has been postulated to contribute to the development of a range of diabetic complications including nephropathy, retinopathy and neuropathy. Several potential drug candidates as AGE inhibitors have been reported recently. Aminoguanidine is the first drug extensively studied both in vitro and in vivo. We have developed a new class of compounds as potent inhibitors of glycation and AGE formation. The novel inhibitors reported here are aryl (and heterocyclic) ureido, and aryl (and heterocyclic) carboxamido phenoxy isobutyric acids and related molecules, which were found by in vitro assay methods to be potent inhibitors of multiple stage of glycation and AGE formation.