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.
Pharmacology Department, Sapporo Breweries, Ltd., Shizuoka, Japan.
T
T
Matsui
Y
Y
Nakamura
H
H
Ishikawa
A
A
Matsuura
F
F
Kobayashi
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