SPR-210 (2-[4-(4,5,7-trifluorobenzothiazol-2-yl)methyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl]
acetic acid), a novel
aldose reductase (AR) inhibitor, exhibited highly potent inhibition of partially purified AR from porcine lens (IC50 = 9.5 x 10(-9) M) and human placenta (IC50 = 1.0 x 10(-8) M). 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 x 10(-8) M).
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 (1-30 mg/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.