Abstract
A series of spiro[imidazolidine-4,4'(1'H)-quinazoline]- 2,2'5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'-halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'-chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline] -2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure-activity relationships in this series are also discussed.
MeSH terms
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Aldehyde Reductase / antagonists & inhibitors*
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Animals
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Imidazoles / toxicity
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Imidazolidines*
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Lens, Crystalline / drug effects
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Lens, Crystalline / enzymology
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Lens, Crystalline / metabolism
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Male
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Mathematics
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Mice
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Molecular Conformation
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Molecular Structure
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Polymers / metabolism
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Quinazolines / chemical synthesis*
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Quinazolines / pharmacology
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Quinazolines / toxicity
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Rabbits
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Rats
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Rats, Inbred Strains
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Sciatic Nerve / drug effects
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Sciatic Nerve / metabolism
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / pharmacology
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Spiro Compounds / toxicity
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Structure-Activity Relationship
Substances
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Imidazoles
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Imidazolidines
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Polymers
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Quinazolines
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Spiro Compounds
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polyol
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6'-chloro-3'-methylspiro(imidazolidine-4,4'(1'H)-quinazoline)-2,2',5(3'H)-trione
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Aldehyde Reductase