Yamagishi M, Yamada Y, Ozaki K, Asao M, Shimizu R, Suzuki M, Matsumoto M, Matsuoka Y, Matsumoto K
Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
J Med Chem. 1992 May 29;35(11):2085-94. doi: 10.1021/jm00089a021.
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.
制备了一系列螺[咪唑烷-4,4'(1'H)-喹唑啉]-2,2',5(3'H)-三酮，并对其进行了醛糖还原酶抑制活性测试。发现6'-卤代衍生物是雄性兔晶状体醛糖还原酶的高效体外抑制剂，也是半乳糖血症大鼠坐骨神经多元醇积累的体内抑制剂。其中，(4R)-6'-氯-3'-甲基螺[咪唑烷-4,4'(1'H)-喹唑啉]-2,2',5(3'H)-三酮(67)表现出最强的体外和体内活性。在使用小鼠和大鼠的初步急性毒性研究中，口服3 g/kg的化合物67既未导致死亡，也未引起行为异常。化合物67被选为进一步评估的候选物。还讨论了该系列中的定量构效关系。
