Highly selective aldose reductase inhibitors .2. Optimization of the aryl part of 3-(arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic acids

Accumulation of intracellular sorbitol, the product of glucose reduction catalyzed by aldose reductase (AR) [EC 1.1.1.21], is thought to be the main culprit in the development of diabetic complications, A series of 3-arylalkyl-2,4,5-trioxoimidazolidine-1-acetic acids was prepared and tested for inhibitory activities towards AR and aldehyde reductase (ALR) [EC 1.1.1.2]. These derivatives showed strong inhibitory activity against AR without markedly inhibiting ALR, In particular, the compounds with 3-nitrophenyl, 4-chloro-3-nitrophenyl, and chloro-substituted benzothiazolyl groups as the aryl part showed powerful AR-inhibitory activity, The chlorosubstituted benzothiazolyl compound showed an AR selectivity of more than 5000 fold.