Abstract
SPR-210 {2-[4-(4, 5, 7-trifluorobenzothiazol-2-yl)methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzo-thiazin-2-yl] acetic acid}, a novel aldose reductase (AR) inhibitor, exhibited highly potent inhibition of partially purified AR from porcine lens (IC50=9.5×10-9 M) and human placenta (IC50=1.0×10-8M). On the other hand, very weak inhibition by SPR-210 was observed against human placenta aldehyde reductase, which is the most closely related enzyme to AR, and against several adeninenucleotide-requiring enzymes. SPR-210 showed a noncompetitive mechanism with respect to DL-glyceraldehyde against porcine lens AR. Sorbitol accumulation in isolated human erythrocytes was effectively inhibited by SPR-210 during incubation with 50 mM glucose (IC50=1.6×10-8M). Oral administration of SPR-210 (1-30 mg/kg/day for 5 days) to streptozotocin-induced diabetic rats decreased the sorbitol contents in the sciatic nerve and lens (ED50=1.9 and 6.8 mg/kg/day, respectively). SPR-210 had higher potency in the lens than other AR inhibitors. Moreover, the deterioration in motor nerve conduction velocity in diabetic rats was ameliorated by treatment with SPR-210 (1-30mg/kg/day) accompanying the reduction in sorbitol content in the sciatic nerve. SPR-210 induced the recovery of the delayed peak latency of oscillatory potentials (O1 O4) in the electroretinogram in diabetic rats (10 mg/kg/day). These results suggest that the specific AR inhibitor SPR-210 will be a useful therapeutic agent for preventing and improving some diabetic complications, especially diabetic neuropathy and retinopathy, and therefore, can be discriminated from other AR inhibitors.
