HIGHLY SELECTIVE ALDOSE REDUCTASE INHIBITORS .3. STRUCTURAL DIVERSITYOF 3-(ARYLMETHYL)-2,4,5-TRIOXOIMIDAZOLIDINE-1-ACETIC ACIDS

Accumulation of intracellular sorbitol, the reduced product of glucose , catalyzed by aldose reductase (AR) (EC 1.1.1.21), is thought to be t he cause of the development of diabetic complications. Our attention i s focused on finding compounds which inhibit AR without significantly inhibiting aldehyde reductase (ALR) (EC 1.1.1.2). The uracil or 2,4-di oxoimidazolidine skeleton having the benzothiazolyl or 4-chloro-3-nitr ophenyl group as an aryl part indicated not only extremely high AR inh ibitory activity but also AR selectivity. The ratio of IC50(ALR)/IC50( AR) of ]-1,2,3,4-tetrahydro-2,4-dioxopyrim-idine-1-acetic acid (47d) w as more than 17 500. The uracil skeleton with the benzothiazolyl moiet y seemed to be the best combination for selective AR inhibition.