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新型醛糖还原酶抑制剂SPR-210的药理特性及其对链脲佐菌素诱导的糖尿病大鼠的影响。

Pharmacological profiles of a novel aldose reductase inhibitor, SPR-210, and its effects on streptozotocin-induced diabetic rats.

作者信息

Matsui T, Nakamura Y, Ishikawa H, Matsuura A, Kobayashi F

机构信息

Pharmacology Department, Sapporo Breweries, Ltd., Shizuoka, Japan.

出版信息

Jpn J Pharmacol. 1994 Feb;64(2):115-24. doi: 10.1254/jjp.64.115.

DOI:10.1254/jjp.64.115
PMID:8028228
Abstract

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.

摘要

SPR - 210(2 - [4 - (4,5,7 - 三氟苯并噻唑 - 2 - 基)甲基 - 3 - 氧代 - 3,4 - 二氢 - 2H - 1,4 - 苯并噻嗪 - 2 - 基]乙酸)是一种新型醛糖还原酶(AR)抑制剂,对猪晶状体部分纯化的AR表现出高效抑制作用(IC50 = 9.5×10⁻⁹ M),对人胎盘的AR也有高效抑制作用(IC50 = 1.0×10⁻⁸ M)。另一方面,观察到SPR - 210对与人胎盘醛糖还原酶(与AR关系最密切的酶)以及几种需要腺嘌呤核苷酸的酶的抑制作用非常弱。SPR - 210对猪晶状体AR而言,对DL - 甘油醛表现出非竞争性抑制机制。在与50 mM葡萄糖孵育期间,SPR - 210有效抑制了分离的人红细胞中的山梨醇积累(IC50 = 1.6×10⁻⁸ M)。对链脲佐菌素诱导的糖尿病大鼠口服SPR - 210(1至30 mg/kg/天,共5天)可降低坐骨神经和晶状体中的山梨醇含量(ED50分别为1.9和6.8 mg/kg/天)。SPR - 210在晶状体中的效力高于其他AR抑制剂。此外,糖尿病大鼠运动神经传导速度的恶化通过SPR - 210(1至30 mg/kg/天)治疗得到改善,同时坐骨神经中山梨醇含量降低。SPR - 210可使糖尿病大鼠视网膜电图中振荡电位(O1 - O4)延迟的峰潜伏期恢复(10 mg/kg/天)。这些结果表明,特异性AR抑制剂SPR - 210将是预防和改善某些糖尿病并发症,尤其是糖尿病神经病变和视网膜病变的有用治疗药物,因此,可与其他AR抑制剂区分开来。

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