Highly Selective Aldose Reductase Inhibitors. 1. 3-(Arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic Acids

A series of 3-(arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic acids (1) was prepared and tested for aldose reductase (AR) and aldehyde reductase (ALR) inhibitory activities. These compounds showed strong inhibitory activity against AR without significant inhibitory activity for ALR. The ratio of IC50...

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Published inJournal of medicinal chemistry Vol. 39; no. 9; pp. 1924 - 1927
Main Authors Ishii, Akira, Kotani, Takayuki, Nagaki, Yasuhiro, Shibayama, Yoji, Toyomaki, Yoshio, Okukado, Nobuhisa, Ienaga, Kazuharu, Okamoto, Kaoru
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 26.04.1996
Amer Chemical Soc
Subjects
Acetates - chemistry
Acetates - pharmacology
Aldehyde Reductase - antagonists & inhibitors
Animals
Biological and medical sciences
Chemistry, Medicinal
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General and cellular metabolism. Vitamins
Guinea Pigs
Kidney - enzymology
Lens, Crystalline - enzymology
Life Sciences & Biomedicine
Magnetic Resonance Spectroscopy
Mass Spectrometry
Medical sciences
Pharmacology & Pharmacy
Pharmacology. Drug treatments
Rats
Science & Technology
DIABETIC COMPLICATIONS
HUMAN PSOAS MUSCLE
ALDEHYDE REDUCTASE
PURIFICATION
Imidazole derivatives
Rat
Enzyme
Nitrogen heterocycle
Diabetes mellitus
Rodentia
Enzyme inhibitor
)
In vitro
Biological activity
Carbamoylation
Prevention
Vertebrata
Mammalia
Cyclization
Structure activity relation
Carboxylic acid
Animal
Aldehyde reductase
Complication
Alcohol dehydrogenase (NADP
Lens
Oxidoreductases
Chemical synthesis
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Summary:A series of 3-(arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic acids (1) was prepared and tested for aldose reductase (AR) and aldehyde reductase (ALR) inhibitory activities. These compounds showed strong inhibitory activity against AR without significant inhibitory activity for ALR. The ratio of IC50(ALR)/IC50(AR) was >1000 in some compouds. On the basis of pharmacological tests such as the recovery of reduced motor nerve conduction velocity and toxicological profile, 3-(3-nitrobenzyl)-2,4,5-trioxoimidazolidine-1-acetic acid (NZ-314) was selected as the candidate for clinical development.
Bibliography:ark:/67375/TPS-VNF9DSRK-T
Abstract published in Advance ACS Abstracts, March 15, 1996.
istex:DBD3717035D3F06770EDA45E3E508CB7B50B1DBA
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9508393