| Size | Price | Stock | Qty |
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| 5mg |
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| Targets |
Zenarestat targets aldose reductase, the first and rate-limiting enzyme of the polyol pathway. Aldose reductase converts glucose to sorbitol, and its overactivity under hyperglycemic conditions is implicated in the pathogenesis of diabetic complications, including neuropathy and cataract. By inhibiting aldose reductase, Zenarestat reduces sorbitol accumulation and prevents downstream tissue damage.
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| ln Vitro |
In vitro, Zenarestat acts as a potent aldose reductase inhibitor. Its activity is assessed using enzyme inhibition assays with purified aldose reductase and a suitable substrate, such as DL-glyceraldehyde or glucose. The compound's ability to inhibit the enzyme's activity is quantified by measuring the reduction in NADPH oxidation or product formation.
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| ln Vivo |
In a dose-dependent manner, zenarestat (3.2, 32 mg/kg; oral; once daily for 8 weeks) suppresses the buildup of neurosorbide [1].
In vivo, Zenarestat improves diabetic peripheral neuropathy in Zucker diabetic fatty rats. As an orally active compound, it has been studied for its potential to prevent or reverse diabetic complications, particularly neuropathy and cataract, by inhibiting aldose reductase and reducing sorbitol accumulation. |
| Enzyme Assay |
In vitro enzyme inhibition assays for Zenarestat are performed using purified aldose reductase enzyme. The enzyme is incubated with a substrate (e.g., DL-glyceraldehyde) and NADPH in the presence of increasing concentrations of the compound. The decrease in NADPH absorbance at 340 nm is measured spectrophotometrically, and the IC50 is calculated from the inhibition curve. These assays quantify the compound's potency as an aldose reductase inhibitor.
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| Cell Assay |
In vitro cellular assays for Zenarestat are performed using cells that express aldose reductase, such as lens epithelial cells or Schwann cells, under high-glucose conditions. Cells are treated with the compound, and intracellular sorbitol levels are measured using enzymatic or HPLC methods. The compound's ability to reduce sorbitol accumulation in cells is assessed, providing a functional measure of aldose reductase inhibition.
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| Animal Protocol |
Animal/Disease Models: Zucker diabetic fat (ZFD) rat (type 2 diabetes model) [1]
Doses: 3.2, 32 mg/kg Route of Administration: Po; one time/day for 8 weeks Experimental Results: At 3.2 mg/kg dose , although the accumulation of sorbitol in the sciatic nerve was diminished, zenarestat had no significant effect on the delay of F-wave minimum latency (FML) and the slowing of motor nerve conduction velocity (MNCV). Partially inhibited in ZDF rats. Treatment with 32 mg/kg zenarestat improved these neurological deficits in ZDF rats, while neurosorbitol accumulation was diminished to almost the level of lean rats. In vivo animal experiments for Zenarestat are conducted in Zucker diabetic fatty rats, a model of type 2 diabetes and diabetic neuropathy. A typical protocol involves oral administration of the compound to diabetic rats, followed by assessment of nerve function (e.g., nerve conduction velocity), histological analysis of nerve tissues, and measurement of sorbitol levels in target tissues. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of Zenarestat have been characterized in preclinical studies. It is an orally active compound with a molecular weight of 441.64 and molecular formula C17H11BrClFN2O4. The compound is soluble in DMSO. Further PK details, including half-life, bioavailability, and tissue distribution, are available from the manufacturer's data sheets.
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| Toxicity/Toxicokinetics |
The toxicity profile of Zenarestat has been evaluated in preclinical studies. As an aldose reductase inhibitor, its safety profile is characterized by its effects on the polyol pathway and potential for off-target effects. Specific toxicity data, including organ-specific effects and dose-limiting toxicities, are typically assessed in standard toxicology studies to support its development as a therapeutic agent.
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| References | |
| Additional Infomation |
Drug Indication
Zenarestat has been investigated for the treatment of diabetic neuropathy. Mechanism of Action Polyneuropathy, or damage to peripheral neurons, is common in diabetic patients and can cause pain, sensory and motor dysfunction in the extremities. Zenarestat is an aldose reductase inhibitor that inhibits glucose metabolism via the polyol pathway, potentially slowing or mitigating the progression of polyneuropathy. Chronic hyperglycemia affects peripheral nerves through extracellular mechanisms (involving multiple glycation reactions and chemical rearrangements) and intracellular pathways (involving increased glucose consumption via the polyol pathway). The polyol pathway enables cells to utilize glucose to produce fructose, and this pathway involves two steps requiring energy and enzymes. In the first step, aldose reductase catalyzes the conversion of glucose to sorbitol; the second step involves the oxidation of nicotinamide adenine dinucleotide phosphate (NADPH to NADP). Chronic hyperglycemia causes damage by activating the polyol pathway, leading to decreased intracellular NADPH levels. This, in turn, reduces the levels of glutathione (a free radical scavenger) and nitric oxide (a vasodilator), while simultaneously increasing intracellular sorbitol levels. This results in decreased inositol (essential for Na-K ATPase function) levels and increased fructose levels, thereby increasing the production of AGEs (advanced glycation end products, byproducts of the polyol pathway). Zenarestat prevents these harmful processes by inhibiting the first step of the polyol pathway. Zenarestat is also known as CI-1014, FK-366, and FR-74366. It was developed for the treatment of diabetic complications, particularly diabetic neuropathy and cataract. The monograph for this compound has been retired and is no longer subject to revision or update. This product is for research use only. |
| Molecular Formula |
C17H11BRCLFN2O4
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|---|---|
| Molecular Weight |
441.6374
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| Exact Mass |
439.957
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| CAS # |
112733-06-9
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| PubChem CID |
5724
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| Appearance |
White to off-white solid powder
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| Density |
1.737g/cm3
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| Boiling Point |
624.4ºC at 760mmHg
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| Flash Point |
331.4ºC
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| Vapour Pressure |
1.86E-16mmHg at 25°C
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| Index of Refraction |
1.659
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| LogP |
2.851
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
595
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
SXONDGSPUVNZLO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H11BrClFN2O4/c18-10-2-1-9(13(20)5-10)7-22-16(25)12-4-3-11(19)6-14(12)21(17(22)26)8-15(23)24/h1-6H,7-8H2,(H,23,24)
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| Chemical Name |
2-[3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-2,4-dioxoquinazolin-1-yl]acetic acid
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| Synonyms |
CI-1014 FK-366 FR-74366 FR 74366 FK366 CI1014 FR74366
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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 : ~100 mg/mL (~226.43 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 25 mg/mL (56.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 250.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.66 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |
*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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