Highly selective aldose reductase inhibitors. II. 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 chloro-substituted benzothiazolyl compound showed an AR selectivity of more than 5,000 fold.
Kotani
T
T
Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Company Ltd., Hyogo, Japan.
Ishii
A
A
Nagaki
Y
Y
Toyomaki
Y
Y
Yago
H
H
Suehiro
S
S
Okukado
N
N
Okamoto
K
K
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006827:Hydantoins; D007093:Imidazoles / Q000737:chemistry*; D007668:Kidney / Q000201:enzymology; D007908:Lens, Crystalline / Q000201:enzymology; D051381:Rats
D004791:Enzyme Inhibitors; D006827:Hydantoins; D007093:Imidazoles; C005411:parabanic acid; D000449:Aldehyde Reductase