Effects of two new aldose reductase inhibitors, AL-1567 and AL-1576, in diabetic rats

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.