Highly selective aldose reductase inhibitors. 3. Structural diversity of 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 the cause of the development of diabetic complications. Our attention is focused on finding compounds which inhibit AR without significantly inhibiting aldehyde reductase (ALR) (EC 1.1.1.2). The uracil or 2,4-dioxoimidazolidine skeleton having the benzothiazolyl or 4-chloro-3-nitrophenyl group as an aryl part indicated not only extremely high AR inhibitory activity but also AR selectivity. The ratio of IC50(ALR)/IC50(AR) of 3-[(5-chlorobenzothiazol-2-yl)methyl]-1,2,3,4-tetrahydro-2,4- dioxopyrimidine-1-acetic acid (47d) was more than 17 500. The uracil skeleton with the benzothiazolyl moiety seemed to be the best combination for selective AR inhibition.
Kotani
T
T
Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Company Ltd., Hyogo, Japan.
Nagaki
Y
Y
Ishii
A
A
Konishi
Y
Y
Yago
H
H
Suehiro
S
S
Okukado
N
N
Okamoto
K
K
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D048909:Diabetes Complications; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D007908:Lens, Crystalline / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013012:Sorbitol / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C105123:3-((5-chlorobenzothiazol-2-yl)methyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-1-acetic acid; D000085:Acetates; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010793:Phthalazines; D011744:Pyrimidinones; D013844:Thiazoles; C067172:zopolrestat; D013012:Sorbitol; D000449:Aldehyde Reductase