Fidarestat (SNK 860)
(Synonyms: 非达司他,SNK 860) 目录号 : GC31487
An aldose reductase inhibitor
Cas No.:136087-85-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Fidarestat is an aldose reductase inhibitor (IC50 = 0.026 μM using human recombinant enzyme) that also inhibits aldo-keto reductase family 1 member B10 (AKR1B10; IC50 = 33 μM using human recombinant enzyme).1 It decreases sorbitol and myo-inositol levels in the sciatic nerve of rats with diabetes induced by streptozotocin when administered at a dose of 2 mg/kg per day.2 Fidarestat (2 mg/kg per day) decreases nerve fiber abnormalities and reverses slowing of motor nerve conduction velocity (MNCV) in an STZ-induced diabetic rat model of peripheral neuropathy. It decreases the pain threshold in STZ-induced diabetic mice that overexpress human aldose reductase when administered at 4 mg/kg per day.3 Fidarestat (50 mg/kg per day) decreases metastasis in a KM20 human colorectal cancer mouse xenograft model.4
1.Ruiz, F.X., Cousido-Siah, A., Mitschler, A., et al.X-ray structure of the V301L aldo-keto reductase 1B10 complexed with NADP+ and the potent aldose reductase inhibitor fidarestat: Implications for inhibitor binding and selectivityChem. Biol. Interact.202(1-3)178-185(2013) 2.Kato, N., Mizuno, K., Matsubara, A., et al.Effect of long-term treatment with a new aldose reductase inhibitor, (2S,4S)-6-fluoro-2',5'-dioxospiro-[chroman-4,4'-imidazolidine]-2-carbox amide (SNK-860), on peripheral neuropathy in streptozotocin-induced diabetic ratsJ. Diabetes Complications8(1)27-32(1994) 3.Uehara, K., Yamagishi, S., Otsuki, S., et al.Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic miceDiabetes53(12)3239-3247(2004) 4.Tammali, R., Reddy, A.B., Saxena, A., et al.Inhibition of aldose reductase prevents colon cancer metastasisCarcinogenesis32(8)1259-1267(2011)
| Cas No. | 136087-85-9 | SDF | |
| 别名 | 非达司他,SNK 860 | ||
| Canonical SMILES | O=C1NC(N[C@@]12C3=C(C=CC(F)=C3)O[C@H](C(N)=O)C2)=O | ||
| 分子式 | C12H10FN3O4 | 分子量 | 279.22 |
| 溶解度 | DMSO: 250 mg/mL (895.35 mM) | 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 | 3.5814 mL | 17.907 mL | 35.8141 mL |
| 5 mM | 0.7163 mL | 3.5814 mL | 7.1628 mL |
| 10 mM | 0.3581 mL | 1.7907 mL | 3.5814 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
[Fidarestat (SNK-860)]
Fidarestat. Aldos, SK 860, SNK 860
Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients
Sorbitol accumulation in nerves has been regarded as one of the major causes of diabetic neuropathy. In this study, fidarestat (SNK-860; 1 mg daily), a potent new aldose reductase inhibitor (ARI), or the commercially available ARI epalrestat (150 mg daily), was administered for 4 weeks to 58 Type 2 diabetic patients. Treatment with these drugs had no effect on glycemic control, judging from plasma glucose and HbA(1c) levels. However, fidarestat treatment normalized the elevated sorbitol content of erythrocytes under fasting as well as postprandial conditions. In contrast, the effect of epalrestat was minimal. There were no major side effects with fidarestat. Thus, fidarestat is considered to be a potent and promising ARI, possibly useful for both preventing and treating diabetic neuropathy. Further studies are needed to clarify how much the occurrence and progression of diabetic neuropathy are inhibited by normalizing sorbitol elevation with fidarestat treatment.
Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-汐1/mTOR pathway
Although hyperglycemia-mediated death and dysfunction of endothelial cells have been reported to be a major cause of diabetes associated vascular complications, the mechanisms through which hyperglycemia cause endothelial dysfunction is not well understood. We have recently demonstrated that aldose reductase (AR, AKR1B1) is an obligatory mediator of oxidative and inflammatory signals induced by growth factors, cytokines and hyperglycemia. However, the molecular mechanisms by which AR regulates hyperglycemia-induced endothelial dysfunction is not well known. In this study, we have investigated the mechanism(s) by which AR regulates hyperglycemia-induced endothelial dysfunction. Incubation of human umbilical vein endothelial cells (HUVECs) with high glucose (HG) decreased the cell viability and inhibition of AR prevented it. Further, AR inhibition prevented the HG-induced ROS generation and expression of BCL-2, BAX and activation of Caspase-3 in HUVECs. AR inhibition also prevented the adhesion of THP-1 monocytes on HUVECs, expression of iNOS and eNOS and adhesion molecules ICAM-1 and VCAM-1 in HG-treated HUVECs. Further, AR inhibition restored the HG-induced depletion of SIRT1 in HUVECs and increased the phosphorylation of AMPK汐1 along-with a decrease in phosphorylation of mTOR in HG-treated HUVECs. Fidarestat decreased SIRT1 expression in HUVECs pre-treated with specific SIRT1 inhibitor but not with the AMPK汐1 inhibitor. Similarly, knockdown of AR in HUVECs by siRNA prevented the HG-induced HUVECs cell death, THP-1 monocyte adhesion and SIRT1 depletion. Furthermore, fidarestat regulated the phosphorylation of AMPK汐1 and mTOR, and expression of SIRT1 in STZ-induced diabetic mice heart and aorta tissues. Collectively, our data suggest that AR regulates hyperglycemia-induced endothelial death and dysfunction by altering the ROS/SIRT1/AMPK汐1/mTOR pathway.
Effects of a Novel Aldose Reductase Inhibitor, Fidarestat (SNK-860), on Vibration Perception Threshold and Subjective Symptoms in Patients with Diabetic Polyneuropathy : An Open-Label Pilot Study
Objective: To evaluate the effects of fidarestat (SNK-860) on vibration perception threshold, as measured by C64 quantitative tuning fork (64Hz) analysis, as well as its effects on subjective symptoms in patients with diabetic polyneuro-pathy.
Design and setting: Open-label, prospective study conducted at 12 hospitals in the central area of Honshu, Japan.
Interventions: Fidarestat was administered at a dosage of 1mg once daily after breakfast for 28 weeks.
Main outcome measures: Vibration perception threshold of upper and lower extremities was determined using a C64 quantitative tuning fork, and measured at baseline and after 12 and 28 weeks of treatment. Subjective symptoms, including numbness, spontaneous pain and hypoaesthesia, were evaluated every 4 weeks.
Results: Subjective symptoms were evaluated in 22 patients, and vibration perception threshold data were available for 19 patients. Vibration perception threshold at baseline was negatively correlated with the severity of the following subjective symptoms: numbness in the upper limbs, and numbness, coldness and hot flushes, smarting pain causing difficulty walking and hypoaesthesia in the lower limbs. During treatment with fidarestat, vibration perception threshold increased significantly in the upper (p = 0.0017) and lower (p = 0.0001) limbs. The following symptoms were also significantly improved: severity of numbness in the lower limbs, heaviness in the foot, coldness and hot flushes in the lower limbs, smarting pain causing difficulty walking, sensation as if walking on sand, sensation as if walking on an uneven road, spontaneous pain in the lower limbs, and dizziness. Adverse events occurred in four patients.
Conclusion: Administration of fidarestat after breakfast was effective in significantly alleviating some symptoms of diabetic polyneuropathy. The C64 quantitative tuning fork analysis is useful in the diagnosis of diabetic polyneuropathy, and as a measure of the severity of the neuropathological symptoms of this condition.