Griffin B W, McNatt L G, Chandler M L, York B M
Metabolism. 1987 May;36(5):486-90. doi: 10.1016/0026-0495(87)90048-5.
Two new potent aldose reductase inhibitors, AL-1567 (DL-spiro(2-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione) and AL-1576 (spiro-(2,7-difluoro-9H-fluoren-9,4'-imidazolidine)2',5'-dione), have been characterized with respect to in vitro activity toward rat lens and human placental aldose reductase and in vivo activity in uncontrolled, severely diabetic rats dosed acutely with the compounds. The IC50 values for inhibition of rat lens aldose reductase are 2.7 X 10(-8) mol/L for AL-1567 and 8.5 X 10(-9) mol/L for AL-1576; very similar IC50 values were measured for each compound with the human placental enzyme. When the compounds were administered orally once per day to 3-week diabetic rats for a period of eight days, the ED50 values for normalization of lens sorbitol levels were 0.60 mg/kg for AL-1567 and 0.05 mg/kg for AL-1576, and for normalization of sciatic nerve sorbitol levels; 0.22 mg/kg for AL-1567 and 0.04 mg/kg for AL-1576. Compared with published data on other aldose reductase inhibitors evaluated in very similar diabetic rat models, both compounds have unusually high activity in lens, and AL-1576 appears to be the most active such compound in both lens and sciatic nerve reported thus far. The evidence linking increased sorbitol pathway activity to diabetic complications, such as cataract and neuropathy in animal models, suggests that aldose reductase inhibitors will be useful therapeutic agents in human diabetics.
两种新型强效醛糖还原酶抑制剂，AL - 1567（DL - 螺环(2 - 氟 - 9H - 芴 - 9,4'-咪唑啉)-2',5'-二酮）和AL - 1576（螺环-(2,7 - 二氟 - 9H - 芴 - 9,4'-咪唑啉)2',5'-二酮），已针对其对大鼠晶状体和人胎盘醛糖还原酶的体外活性以及在未控制的严重糖尿病大鼠中急性给予化合物后的体内活性进行了表征。抑制大鼠晶状体醛糖还原酶的IC50值，AL - 1567为2.7×10(-8) mol/L，AL - 1576为8.5×10(-9) mol/L；用这两种化合物对人胎盘酶进行测定时，测得的IC50值非常相似。当每天给3周龄糖尿病大鼠口服一次这些化合物，持续8天时，使晶状体山梨醇水平恢复正常的ED50值，AL - 1567为0.60 mg/kg，AL - 1576为0.05 mg/kg；使坐骨神经山梨醇水平恢复正常的ED50值，AL - 1567为0.22 mg/kg，AL - 1576为0.04 mg/kg。与在非常相似的糖尿病大鼠模型中评估的其他醛糖还原酶抑制剂的已发表数据相比，这两种化合物在晶状体中具有异常高的活性，并且AL - 1576似乎是迄今为止报道的在晶状体和坐骨神经中活性最高的此类化合物。在动物模型中，将山梨醇途径活性增加与糖尿病并发症（如白内障和神经病变）联系起来的证据表明，醛糖还原酶抑制剂将成为人类糖尿病患者有用的治疗药物。
