Miwa I, Hirano M, Inagaki K, Belbeoc'h C, Okuda J
Biochem Pharmacol. 1987 Sep 1;36(17):2789-94. doi: 10.1016/0006-2952(87)90266-8.
Seventeen hydantoin derivatives were tested as inhibitors of aldose reductase, an enzyme believed to participate in the initiation of diabetic complications. Nine compounds with high inhibitory activities (IC50 values against purified rat lens aldose reductase less than or equal to 1.06 X 10(-6)M) were tested further for their abilities to prevent sorbitol accumulation induced by exposure of excised rat lens and sciatic nerve to a high glucose concentration (50 mM). Seven active compounds among them inhibited sorbitol accumulation by about 50% or more at a concentration of 10(-5)M. These seven compounds were given orally to streptozotocin-induced diabetic rats at a dose of 50 mg/kg/day and were assessed for their abilities to prevent both sorbitol accumulation in two tissues (lens and sciatic nerve) and myo-inositol depletion in the sciatic nerve. 1-[(2,4,5-Trichlorophenyl)sulfonyl]hydantoin, 1-[(2,5-dichlorophenyl)sulfonyl]hydantoin, and 1-[(beta-naphthyl)sulfonyl]hydantoin were found to be the most effective: they inhibited sorbitol accumulation in the sciatic nerve completely and that in the lens by more than 92%. It is conceivable from this study that the three compounds are promising for further investigation targeted to the treatment of diabetic complications.
十七种乙内酰脲衍生物作为醛糖还原酶抑制剂进行了测试，醛糖还原酶被认为参与糖尿病并发症的引发过程。对九种具有高抑制活性的化合物（对纯化的大鼠晶状体醛糖还原酶的IC50值小于或等于1.06×10⁻⁶M）进一步测试了它们预防由切除的大鼠晶状体和坐骨神经暴露于高葡萄糖浓度（50 mM）所诱导的山梨醇积累的能力。其中七种活性化合物在10⁻⁵M浓度下可抑制山梨醇积累约50%或更多。以50 mg/kg/天的剂量将这七种化合物口服给予链脲佐菌素诱导的糖尿病大鼠，并评估它们预防两种组织（晶状体和坐骨神经）中山梨醇积累以及坐骨神经中肌醇消耗的能力。发现1-[(2,4,5-三氯苯基)磺酰基]乙内酰脲、1-[(2,5-二氯苯基)磺酰基]乙内酰脲和1-[(β-萘基)磺酰基]乙内酰脲最为有效：它们完全抑制坐骨神经中的山梨醇积累，并且抑制晶状体中的山梨醇积累超过92%。从这项研究可以推测，这三种化合物有望针对糖尿病并发症的治疗进行进一步研究。
