Zenarestat
(Synonyms: 折那司他) 目录号 : GC63990
Zenarestat 是一种有效的、具有口服活性的醛糖还原酶 (aldose reductase) 抑制剂。Zenarestat 改善 Zucker 糖尿病脂肪大鼠的糖尿病周围神经病变。
Cas No.:112733-06-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Zenarestat is a potent and orally active aldose reductase inhibitor. Zenarestat improves diabetic peripheral neuropathy in Zucker diabetic fatty rats[1].
Zenarestat (3.2, 32 mg/kg; p.o.; daily for 8 weeks) inhibits nerve sorbitol accumulation in a dose-dependent manner[1].
[1]. Shimoshige Y, et al. The effects of zenarestat, an aldose reductase inhibitor, on peripheral neuropathy in Zucker diabetic fatty rats. Metabolism. 2000;49(11):1395-1399.
| Cas No. | 112733-06-9 | SDF | Download SDF |
| 别名 | 折那司他 | ||
| 分子式 | C17H11BrClFN2O4 | 分子量 | 441.64 |
| 溶解度 | DMSO : 100 mg/mL (226.43 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2643 mL | 11.3214 mL | 22.6429 mL |
| 5 mM | 0.4529 mL | 2.2643 mL | 4.5286 mL |
| 10 mM | 0.2264 mL | 1.1321 mL | 2.2643 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
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工作液浓度： mg/ml；
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2.
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Enzymatic hydrolysis of Zenarestat 1-O-acylglucuronide
J Pharm Pharmacol 1994 Mar;46(3):235-9.PMID:8027935DOI:10.1111/j.2042-7158.1994.tb03786.x.
Zenarestat, (3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-1-yl) acetic acid, an aldose reductase inhibitor is metabolized mainly to the glucuronide in rat and man. The glucuronide was purified from urine of volunteers after ingestion of Zenarestat. The structure of the glucuronide was confirmed by LC-MS and NMR as 1-O-acyl-beta-glucuronide. This compound was unstable at physiological pH, being converted to its structural isomers and the aglycone with half-life of 25 min at pH 7.4 and 37 degrees C in aqueous solution. Enzymatic hydrolysis of the glucuronide was studied in urine, blood and tissues. beta-Glucuronidase in human urine contributed little to the hydrolysis of the glucuronide, while in rat urine at pH 6, it was degraded by beta-glucuronidase and the formation of Zenarestat was clearly faster than its formation in buffer at pH 6. In both rat and human blood, these reactions were accelerated by albumin, although rat red blood cells may also contribute. The rate of degradation was not affected by red blood cell membrane, haemoglobin, globulin, esterases or beta-glucuronidase. Arylesterase in rat liver, arylesterase and acetylcholinesterase in the kidney, and beta-glucuronidase in both tissues may contribute. Thus, enzymatic degradation of Zenarestat 1-O-acyl-beta-glucuronide is dependent not only on pH and temperature but also on species and the type of tissue or body fluid.
Effect of Zenarestat, an aldose reductase inhibitor, on endoneurial blood flow in experimental diabetic neuropathy of rat
Neurosci Lett 2001 Sep 14;310(2-3):81-4.PMID:11585572DOI:10.1016/s0304-3940(01)02052-3.
The effects of Zenarestat, an aldose reductase inhibitor, on endoneurial blood flow (NBF) were explored in streptozotocin-induced diabetic rats. Rats were maintained on a diet of containing 0.09% Zenarestat for 8 weeks, then NBF in the sciatic nerve was measured using microelectrode hydrogen polarography. NBF in the diabetic control rats was significantly lower than values in age-matched control rats, however, NBF was not significantly altered in diabetic rats treated with Zenarestat. Direct application of nitric oxide synthase inhibitor, NG-nitro-L-arginine, did not affect NBF in diabetic control rats, whereas this application significantly reduced NBF both in age-matched control and Zenarestat treated diabetic rats. Considerable levels of Zenarestat were confirmed in the sciatic nerve in the drug treated rats. These data suggest that aldose reductase, such as Zenarestat, might restore or prevent the alteration of endoneurial blood flow resulting from an impairment of nitric oxide function.
The effects of Zenarestat, an aldose reductase inhibitor, on peripheral neuropathy in Zucker diabetic fatty rats
Metabolism 2000 Nov;49(11):1395-9.PMID:11092500DOI:10.1053/meta.2000.17723.
We studied the effects of Zenarestat, an aldose reductase inhibitor (ARI), on peripheral neuropathy in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes. ZDF rats and their lean rats counterparts were fed a sucrose-containing diet, and Zenarestat was given orally once a day for 8 weeks. Motor nerve conduction velocity (MNCV), F-wave minimal latency (FML), and sorbitol concentrations in the sciatic nerve were measured. In ZDF control rats, a remarkable accumulation of sorbitol, a delay in FML, and a slowing of MNCV were observed compared with lean rats. At a dose of 3.2 mg/kg, Zenarestat had no significant effect on the delay in FML and the slowing of MNCV, although the sorbitol accumulation in the sciatic nerve was partially inhibited in ZDF rats. On the other hand, 32 mg/kg Zenarestat treatment improved these nerve dysfunctions in ZDF rats, along with a reduction of nerve sorbitol accumulation almost to the level of lean rats. These data showed that Zenarestat improved diabetic peripheral neuropathy in ZDF rats, a type 2 diabetes model, providing evidence for the therapeutic potential of Zenarestat for the treatment of diabetic neuropathy.
Sex difference in the excretion of Zenarestat in mice, rats, dogs and humans
Xenobiotica 1992 Aug;22(8):941-7.PMID:1413883DOI:10.3109/00498259209049900.
1. Mice show a sex difference in the excretion of Zenarestat similar to that seen in rats, but dogs and humans show no significant sex difference. 2. Female rats and mice, and both sexes of dogs and humans, appear to possess an active secretory mechanism in the renal excretion of Zenarestat, which is lacking or relatively inactive in male rats and mice.
Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group
Neurology 1999 Aug 11;53(3):580-91.PMID:10449124DOI:10.1212/wnl.53.3.580.
Objective: To determine whether the aldose reductase inhibitor (ARI) Zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN). Methods: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI Zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies. Results: Dose-dependent increments in sural nerve Zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, Zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 microm) sural nerve myelinated fibers. Conclusions: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as Zenarestat may be required to stop or reverse progression of DPN.