| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 100mg |
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| 250mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
Tolrestat targets aldose reductase, the first enzyme in the polyol pathway, which catalyzes the reduction of glucose to sorbitol. In diabetes, elevated glucose levels lead to increased flux through the polyol pathway, resulting in the accumulation of sorbitol and fructose in tissues. This accumulation contributes to the development of diabetic complications such as neuropathy, nephropathy, retinopathy, and cataracts. By inhibiting aldose reductase with an IC50 of 35 nM, tolrestat reduces sorbitol accumulation and prevents the osmotic and oxidative stress associated with diabetic complications.
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| ln Vitro |
In vitro, tolrestat acts as a potent inhibitor of aldose reductase with an IC50 of 35 nM. The compound's ability to inhibit the enzyme has been demonstrated in cell-free enzymatic assays using purified aldose reductase. By inhibiting aldose reductase, tolrestat reduces the conversion of glucose to sorbitol, thereby preventing the accumulation of sorbitol in cells. These in vitro studies confirm the compound's mechanism of action as an aldose reductase inhibitor.
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| ln Vivo |
In diabetic rats, tolrestat (1.8 mg/kg daily) can restore normal levels of erythrocyte sorbitol [1]. The estimated IDs for sciatic nerve and lens in 21-day diabetic rats were 1.7 and 2.2 for (±)sobinib, and 4.8 and roughly 20 for torestal [2]. Both sobinib and torestat reduced tissue AR activity, but they had no discernible effects on plasma lipoprotein levels, body weight, or overall health in the mice. Mice administered torisstat exhibit a substantial increase in the production of cholesterol-rich foam cells in the aortic root [3].
In vivo, tolrestat has been studied for its efficacy in preventing and treating diabetic complications. Clinical studies have evaluated its effects on diabetic neuropathy, nephropathy, retinopathy, and cataracts. The compound has been shown to reduce sorbitol accumulation in various tissues and improve nerve conduction velocity in diabetic patients. Tolrestat is considered to be effective in treating the consequences of diabetes, including neuropathy, nephropathy, retinopathy, and esophageal motility and vibration perception. |
| Enzyme Assay |
The in vitro enzyme/receptor binding (non-cellular) assays for tolrestat are enzymatic assays using purified aldose reductase enzyme. The enzyme is incubated with its substrate (glucose) and varying concentrations of tolrestat, and the rate of sorbitol production is measured spectrophotometrically. The IC50 for inhibition of aldose reductase activity is determined from the dose-response curve. These assays confirm the compound's direct inhibition of aldose reductase and provide quantitative measures of its potency.
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| Cell Assay |
In vitro cellular assays for tolrestat are performed using cells that express aldose reductase, such as lens epithelial cells, Schwann cells, or renal cells. Cells are cultured in high-glucose conditions to mimic the diabetic state and treated with varying concentrations of tolrestat. Intracellular sorbitol levels are measured using enzymatic or chromatographic methods. Cell viability and oxidative stress markers are also assessed. These assays confirm the compound's ability to reduce sorbitol accumulation and prevent cellular damage in a diabetic environment.
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| Animal Protocol |
In vivo animal experiments for tolrestat are conducted in diabetic animal models, such as streptozotocin-induced diabetic rats or mice. Animals are treated with tolrestat via oral administration, and various endpoints are assessed, including nerve conduction velocity, retinal function, renal function, and cataract formation. Tissue sorbitol levels are measured to confirm target engagement. These studies provide evidence for the compound's efficacy in preventing diabetic complications.
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| ADME/Pharmacokinetics |
Tolrestat has a molecular weight of 357.35 g/mol and a molecular formula of C16H14F3NO3S. The compound is orally active. It is soluble in DMSO at 50 mg/mL and in aqueous formulations at ≥2.5 mg/mL with appropriate solubilizers. Detailed pharmacokinetic parameters such as half-life, Cmax, and bioavailability have been characterized in clinical studies. Tolrestat is metabolized in the liver and excreted via the kidneys.
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| Toxicity/Toxicokinetics |
Tolrestat has been evaluated in clinical studies and has been reported to be generally well-tolerated. Common adverse effects may include gastrointestinal disturbances, headache, and rash. However, the compound's development has been limited by concerns about hepatotoxicity and other adverse effects. Comprehensive toxicology studies have characterized the compound's safety profile, but further optimization may be needed to improve its therapeutic index.
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| References |
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| Additional Infomation |
Tolrestat belongs to the naphthalene family and is an EC 1.1.1.21 (aldose reductase) inhibitor. Tolrestat (INN) (AY-27773) is an aldose reductase inhibitor that was once approved for the control of certain diabetic complications. Although it was approved for marketing in several countries, it failed in a Phase III clinical trial in the United States due to toxicity and ultimately did not receive FDA approval. It was previously marketed under the brand name Alredase, but Wyeth discontinued production of the product in 1997 due to serious hepatotoxicity and the risk of death. Drug Indications Used to control certain diabetic complications.
Tolrestat is a potent, orally active aldose reductase inhibitor with an IC50 of 35 nM. It has been studied for the prevention and treatment of diabetic complications, including neuropathy, nephropathy, retinopathy, and cataracts. By inhibiting aldose reductase, tolrestat reduces sorbitol accumulation in tissues and prevents the osmotic and oxidative stress associated with diabetic complications. Tolrestat is not an approved drug in many countries due to safety concerns, but it remains a valuable research tool for studying the role of aldose reductase in diabetic complications. |
| Molecular Formula |
C16H14F3NO3S
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|---|---|
| Molecular Weight |
357.34746
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| Exact Mass |
357.064
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| CAS # |
82964-04-3
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| PubChem CID |
53359
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
498.1±55.0 °C at 760 mmHg
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| Melting Point |
164-165°
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| Flash Point |
255.0±31.5 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.602
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| LogP |
3.41
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
486
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LUBHDINQXIHVLS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H14F3NO3S/c1-20(8-13(21)22)15(24)11-5-3-4-10-9(11)6-7-12(23-2)14(10)16(17,18)19/h3-7H,8H2,1-2H3,(H,21,22)
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| Chemical Name |
N-(6-methoxy-5-(trifluoromethyl)naphthalene-1-carbonothioyl)-N-methylglycine
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| Synonyms |
AY27,773
AY 27773 Alredase TolrestatumAY-27773 LorestatAY27773 Tolrestat AY-27,773 AY 27,773
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~139.92 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7984 mL | 13.9919 mL | 27.9838 mL | |
| 5 mM | 0.5597 mL | 2.7984 mL | 5.5968 mL | |
| 10 mM | 0.2798 mL | 1.3992 mL | 2.7984 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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