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Zenarestat (FK-366; CI-1014; FR-74366) is a novel and potent aldose reductase inhibitor with the potential to be used for the treatment of diabetic neuropathy and cataract.
| 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].
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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. |
| References | |
| Additional Infomation |
Drug Indication
Investigated for use/treatment in neuropathy (diabetic). Mechanism of Action Polyneuropathy, damage of peripheral neurons, is common in diabetes mellitus patients and causes pain, sensory and motor deficits in the limbs. Zenarestat is an aldose reductase inhibitor which inhibits the metabolism of glucose by the polyol pathway, which possibly slows or reduces progression of polyneuropathy. Chronic hyperglycemia affects peripheral nerves by an extracellular mechanism with many types of glycation reactions and chemical rearrangements, and an intracellular route involving increased amounts of glucose passing through the polyol pathway. The polyol pathway allows cells to produce fructose from glucose, and has two steps, which require energy and enzymes. Aldose reductase catalyzes the conversion of glucose to sorbitol in the first step, while the second involves the oxidation of nicotinamide adenine dicnucleotide phosphate (conversion of NADPH to NADP). Chronic hyperglycemia causes damage by overactivity of the polyol pathway, causing a decrease in cellular NADPH levels, reducing the amount of glutathione (a free radical scavenger), and nitric oxide (a vasodilator), as well as increasing cellular sorbital levels, causing decreased levels of myo-inositol (necessary for Na-K ATPase function) and increased fructose, thus increasing AGE (advanced glycosylation end products), the byproduct of the polyol pathway. The suppression of the first step in the polyol pathway by zenarestat prevents these deleterious processes from occuring. |
| 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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