title: Biological activities and quantitative structure-activity relationships of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones as aldose reductase inhibitors.
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.
authors.affiliation: Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Ozaki
authors.forename: M
authors.initials: M
authors.lastname: Asao
authors.forename: R
authors.initials: R
authors.lastname: Shimizu
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D048289:Imidazolidines; D007908:Lens, Crystalline / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008433:Mathematics; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D011108:Polymers / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D048289:Imidazolidines; D011108:Polymers; D011799:Quinazolines; D013141:Spiro Compounds; C024617:polyol; C074922:6'-chloro-3'-methylspiro(imidazolidine-4,4'(1'H)-quinazoline)-2,2',5(3'H)-trione; D000449:Aldehyde Reductase