Pharmacological Profiles of a Novel Aldose Reductase Inhibitor, SPR-210, and Its Effects on Streptozotocin-Induced Diabetic Rats

Abstract

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 x 10-9 M) and human placenta (IC50=1.0 x 10-'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 incuba tion with 50 mM glucose (IC50=1.6 x 10-'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 in hibitors. 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 (O, 04) 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.

Effects of a Novel Potent Aldose Reductase Inhibitor, GP-1447, on Aldose Reductase Activity In Vitro and on Diabetic Neuropathy and Cataract Formation in Rats.

“…Treatment with GP-1447 dose-dependently amelio rated the slowed MCV with an ED50 value of 0.28 mg/kg/day, indicating that this compound is approxi mately twenty times more potent than SG-210 in restoring the reduced MCV. In contrast to our results, SG-210 has been reported to recover the reduced MCV, the ED50 value being 0.5 mg/kg/day (17). The reason for this dis crepancy is unclear, but may be due to the different methods used.…”

Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats

“…Although several reports in the literature indicate that ARIs inhibit sugar cataracts through the inhibition of enzyme AR (Unakar and Tsui, 1983;Harries et al, 1985;Unakar et al, 1985), many ARIs have side effects when administrated systemically. Moreover, it was previously reported that the effect of AR inhibitors such as epalrestat (Terashima et al, 1984), tolrestat (Simard-Duquesne et al, 1985), zenarestat (Ao et al, 1991), SG-210 (Matsui et al, 1994) and SNK-860 (Mizuno et al, 1992) on cataract formation is inadequate in spite of their potent ameliorating effect on the decreased motor nerve conduction velocity in diabetic animals. Thus, a synthetic compound such as epalrestat is not proper as an anti-cataract drug in diabetic animal model.…”

Hyperglycemia, glycoxidation and receptor for advanced glycation endproducts: potential mechanisms underlying diabetic complications, including diabetes‐associated periodontitis

“…However, in hyperglycemia, markedly increased production of sorbitol ensues. This process has long been hypothesized to be linked to the development of diabetic retinopathy, neuropathy and nephropathy (19,22,47). In certain populations, recognized polymorphisms in the aldose reductase gene have been associated with increased complications (29,39).…”