Pharmacological profiles of a novel aldose reductase inhibitor, SPR-210, and its effects on streptozotocin-induced diabetic rats.
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.
Matsui
T
T
Pharmacology Department, Sapporo Breweries, Ltd., Shizuoka, Japan.
Nakamura
Y
Y
Ishikawa
H
H
Matsuura
A
A
Kobayashi
F
F
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D052160:Benzothiazoles; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000503:physiopathology; D004596:Electroretinography / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000493:pharmacokinetics; D013552:Swine; D013843:Thiazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
D052160:Benzothiazoles; D013843:Thiazines; D013844:Thiazoles; C088258:SPR 210; D013012:Sorbitol; D000449:Aldehyde Reductase