Epalrestat (ONO2235)   中文名称: 益帕瑞司特

Aldose reductase

在雪旺细胞 (SC) 中，依帕司他（100 和 200 µM，24 小时）会吸附细胞活力并引起细胞荧光 [5]。 Epalrestat 在 10 和 50 µM 浓度下激活 Nrf2，在 24 小时内上调 γ-GCS。 SC 环氧水平受到依帕司他（50 µM，16 小时）的保护 [5]。

在八周内，依帕司他（常规饲料中的 0.08%（w/w））可以以 db/db 比预防糖尿病肾病患者的肾炎[4]。依帕司他（每天注射 100 毫克/公斤，持续 6 周）。保护支架免受链脲佐菌素（streptozotocin）对糖尿病周围神经（DPN）造成的损伤[6]。依帕司他（50 mg/kg，每天两次通过阑尾给药）可降低小鼠大脑的梗塞体积和血脑屏障通透性[7]。

RT-PCR[5]
细胞类型：大鼠 SC，从而增加 SC[5] 中的细胞内谷氨酰胺。
测试浓度： 10 或 50 µM
孵育时间： 4 小时
实验结果： 在 10 和 50 µM 浓度下，活性 Nrf2 的核水平增加了 1.8 倍和 3.8 倍，但未能增加 Nrf2 mRNA 水平。

Animal/Disease Models: db/db mice[4]
Doses: 0.08% (w/w) fed regular feed
Doses: 8 weeks
Experimental Results: Improved GBM thickening and mesangial matrix deposition in renal tissue. Reduces elevated sorbitol and fructose in plasma, urine, and renal cortex of db/db mice. Myo-inositol diminished in plasma and urine, whereas it increased in the renal cortex.

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Animal/Disease Models: Rats were fed a high-fat and high-sugar diet for 4 weeks, and streptozotocin was injected at the 4th and 8th weeks [6]
Doses: 100 mg/kg/d
Route of Administration: ig for 6 weeks
Experimental Results: Improved pathological structure of rats Neurites and myelin. SOD, CAT, and GPX protein levels were increased in the sciatic nerve. Reduces aldose reductase levels in the sciatic nerve.

rat LD50 oral 5300 ug/kg Iyakuhin Kenkyu. Study of Medical Supplies., 23(201), 1992
rat LD50 intraperitoneal 922 gm/kg Iyakuhin Kenkyu. Study of Medical Supplies., 23(201), 1992
rat LD50 subcutaneous >3 gm/kg Iyakuhin Kenkyu. Study of Medical Supplies., 23(201), 1992
rat LD50 intravenous 255 ug/kg Iyakuhin Kenkyu. Study of Medical Supplies., 23(201), 1992
mouse LD50 oral 3200 mg/kg Iyakuhin Kenkyu. Study of Medical Supplies., 23(201), 1992

[1]. Ramirez, M.A. and N.L. Borja, Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy, 2008. 28(5): p. 646-55.

[2]. Effects of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy and gastroparesis. Intern Med, 2003. 42(8): p. 655-64.

[3]. Clinical investigation of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy in Japan: multicenter study. Diabetic Neuropathy Study Group in Japan. J Diabetes Complications, 1996. 10(3): p. 168-72.

[4]. The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation. Acta Pharmacol Sin. 2019 Jan;40(1):86-97.

[5]. Epalrestat increases intracellular glutathione levels in Schwann cells through transcription regulation. Redox Biol. 2013 Nov 19;2:15-21.

[6]. Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway. Neural Regen Res. 2016 Feb;11(2):345-51.

[7]. The Aldose Reductase Inhibitor Epalrestat Maintains Blood-Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia. Mol Neurobiol. 2023 Jul;60(7):3741-3757.

Epalrestat is a monocarboxylic acid that is 1,3-thiazolidine which is substituted on the nitrogen by a carboxymethyl group, at positions 2 and 4 by thioxo and oxo groups, respectively, and at position 5 by a 2-methyl-3-phenylprop-2-en-1-ylidene group. It is an inhibitor of aldose reductase (which catalyses the conversion of glucose to sorbitol) and is used for the treatment of some diabetic complications, including neuropathy. It has a role as an EC 1.1.1.21 (aldehyde reductase) inhibitor. It is a member of thiazolidines and a monocarboxylic acid.
Epalrestat is under investigation in clinical trial NCT03244358 (Evaluation of Epalrestat in Metastatic Triple-negative Breast Cancer).
Epalrestat is an orally available, a non-competitive, reversible inhibitor of aldose reductase (AR), with potential antineoplastic, antioxidant, and anti-inflammatory activities. Upon oral administration, epalrestat non-competitively binds to AR, a polyol pathway enzyme that catalyzes reactive oxygen species (ROS)-initiated lipid peroxidation-generated lipid aldehydes and their glutathione conjugates, which have been implicated in the activation of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and activator protein-1 (AP-1), which control the transcription of many inflammatory cytokines. Increased inflammatory cytokines and growth factors promote cell proliferation, a primary feature in the tumorigenesis process. AR is overexpressed in several oxidative stress- and inflammation-related conditions, including cancer.

C15H13NO3S2

319.4

319.033

C, 56.41; H, 4.10; N, 4.39; O, 15.03; S, 20.08

82159-09-9

1549120

Pink to red solid powder

1.4±0.1 g/cm3

516.8±60.0 °C at 760 mmHg

210-217ºC

266.4±32.9 °C

0.0±1.4 mmHg at 25°C

1.706

2.02

115

1

5

4

21

519

0

C/C(=C\C1=CC=CC=C1)/C=C\2/C(=O)N(C(=S)S2)CC(=O)O

CHNUOJQWGUIOLD-NFZZJPOKSA-N

InChI=1S/C15H13NO3S2/c1-10(7-11-5-3-2-4-6-11)8-12-14(19)16(9-13(17)18)15(20)21-12/h2-8H,9H2,1H3,(H,17,18)/b10-7+,12-8-

2-[(5Z)-5-[(E)-2-Methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2 mg/mL (6.26 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。