Highly Selective Aldose Reductase Inhibitors. 3. Structural Diversity of 3-(Arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic Acids
| Autor: | Kaoru Okamoto, Takayuki Kotani, Seishi Suehiro, Akira Ishii, Nobuhisa Okukado, Yasuhiro Nagaki, Yukari Konishi, Hisashi Yago |
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| Rok vydání: | 1997 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Stereochemistry Carboxylic acid Pyrimidinones Acetates Kidney Chemical synthesis Diabetes Complications Structure-Activity Relationship chemistry.chemical_compound Aldehyde Reductase Lens Crystalline Drug Discovery Animals Humans Sorbitol Benzothiazoles Enzyme Inhibitors chemistry.chemical_classification Aldose reductase Molecular Structure biology Aryl Imidazoles Uracil Rats Thiazoles chemistry Enzyme inhibitor biology.protein Phthalazines Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 40:684-694 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm960594+ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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