A HIGHLY SPECIFIC ALDOSE REDUCTASE INHIBITOR, ETHYL 1-BENZYL-3-HYDROXY-2(5H)-OXOPYRROLE-4-CARBOXYLATE, AND ITS CONGENERS

Ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (1, EBPC) is a potent and specific inhibitor of aldose reductase. It was >4000× more potent in its inhibition of rat lens aldose reductase than the closely related rat or pig kidney aldehydr reductase, thus making it the most selective inhibitor of a NADPH-dependent carbonyl reductase identified to date. In agreement with this observation, it was found to be a highly potent inhibitor of aldose reductase from rat sciatic nerve with >98% inhibition at 1 μM, but it was practically devoid of activity against aldehyde reductases from rat liver and brain. Inhibition of aldose reductase was mixed type for glyceraldehyde (K i =8.0×10 −8 M) and noncompetitive for NADPH (K i =1.70×10 −8 M). Its potential as an in vitro tool to quantitate monomeric aldo/keto reductase activities in crude tissue extracts is presented. Structure-activity relationships emerging from synthetic modifications of EBPC are discussed. Several modifications were found to be active in vitro against aldose reductase from human placenta and in vivo in a rat model of diabetic complications, but none was more potent than EBPC