| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg | |||
| 50mg | |||
| 100mg | |||
| 250mg | |||
| Other Sizes |
| Targets |
Aldose reductase (potent inhibitor, IC50 = 100 pM).
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| ln Vitro |
In vitro enzymatic assays demonstrate that AT-007 is a highly potent inhibitor of aldose reductase with an IC50 value of 100 pM. The compound exhibits excellent selectivity for aldose reductase over related aldo-keto reductases. Aldose reductase is the enzyme responsible for the conversion of glucose to sorbitol and galactose to galactitol in the polyol pathway. In the context of galactosemia, the accumulation of galactitol due to aldose reductase activity contributes to the pathophysiology of the disease, including cataract formation and other complications. AT-007's potent inhibition of aldose reductase reduces galactitol production and prevents downstream pathology.
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| ln Vivo |
In GALT reserve organ tissues (liver, brain, and traction), AT-007 markedly decreased galactitol levels but did not raise galactose or Gal1P levels [2].
In vivo studies in GALT-deficient rats, a model of galactosemia, demonstrate that AT-007 reduces toxic galactitol levels and prevents disease complications. The compound's oral bioavailability and brain penetration are critical for its efficacy, as galactosemia affects multiple organ systems including the central nervous system. Treatment with AT-007 has been shown to lower galactitol levels in tissues, including the brain, and to prevent the development of galactosemia-associated complications. These findings support the potential of AT-007 as a therapeutic agent for galactosemia and other diseases involving aldose reductase-mediated toxicity. |
| Enzyme Assay |
Aldose reductase inhibition assays are performed using purified recombinant aldose reductase enzyme and a suitable substrate such as DL-glyceraldehyde or D-glucose. The enzyme is incubated with the substrate and NADPH in the presence of varying concentrations of AT-007. The oxidation of NADPH is measured spectrophotometrically at 340 nm, and the rate of substrate reduction is calculated. IC50 values are determined from dose-response curves by non-linear regression analysis. Selectivity against other aldo-keto reductases is assessed using similar assay formats to confirm the compound's specificity for aldose reductase.
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| Cell Assay |
Cellular assays for AT-007 typically involve culturing cells under conditions that promote polyol pathway activation, such as high glucose or galactose concentrations. Cells are treated with AT-007 at various concentrations, and intracellular galactitol or sorbitol levels are measured using LC-MS/MS or enzymatic assays. The compound's ability to reduce polyol accumulation is quantified, and EC50 values are calculated. Cytotoxicity against mammalian cell lines is assessed in parallel to evaluate selectivity. Neuroprotective effects are evaluated in neuronal cell models exposed to high galactose or glucose concentrations.
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| Animal Protocol |
In vivo efficacy of AT-007 is evaluated in GALT-deficient rat models of galactosemia. Rats are fed a galactose-containing diet to induce galactitol accumulation and disease pathology, and then treated with AT-007 via oral administration. Galactitol levels in tissues including the brain, lens, and liver are measured by LC-MS/MS. Disease complications such as cataract formation are assessed by ophthalmological examination, and neurological function is evaluated using behavioral tests. The compound's ability to prevent or reverse galactosemia-associated pathology is assessed by histopathological examination of affected tissues.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of AT-007 have been characterized in preclinical studies. The compound demonstrates oral bioavailability and brain penetration, which are essential for treating the central nervous system manifestations of galactosemia. Key PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) following oral administration are determined using LC-MS/MS analysis of plasma and brain tissue samples. The compound's favorable pharmacokinetic profile supports its potential for clinical development in galactosemia and other indications involving aldose reductase.
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| Toxicity/Toxicokinetics |
Toxicological evaluation of AT-007 has been conducted in preclinical studies to support its development as a therapeutic agent. Standard toxicology assessments include acute and repeated-dose toxicity studies in rodents and non-rodent species, genotoxicity assays (Ames test, micronucleus test), and reproductive and developmental toxicity studies. The compound's safety profile has been evaluated in GALT-deficient rat models and in healthy animals. As an aldose reductase inhibitor, potential effects on polyol pathway function and glucose metabolism are carefully monitored. The compound's favorable safety profile has supported its advancement into clinical trials for galactosemia.
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| References |
[1]. Maeve Conneighton, et al. Applied Therapeutics Announces Initiation of Phase 1/2 Study of AT-007 in Galactosemia.
[2]. UNITED STATES SECURITIES AND EXCHANGE COMMISSION. APPLIED THERAPEUTICS, INC. |
| Additional Infomation |
Gavorestat is being investigated in the clinical trial NCT04902781 (AT-007: Clinical benefit, safety, pharmacokinetics and pharmacodynamics study in pediatric patients with classic galactosemia).
AT-007 (Govorestat) is an orally active, brain-penetrant aldose reductase inhibitor in development for the treatment of galactosemia, a rare genetic disorder caused by deficiency of galactose-1-phosphate uridyl transferase (GALT). The compound has received regulatory designations including Orphan Drug Designation and Rare Pediatric Disease Designation for the treatment of galactosemia. Clinical trials have been conducted to evaluate the safety and efficacy of AT-007 in patients with galactosemia. Its mechanism of action involves potent inhibition of aldose reductase, which reduces the production of toxic galactitol and prevents disease complications. The compound represents a promising therapeutic approach for managing galactosemia and potentially other aldose reductase-mediated pathologies. |
| Molecular Formula |
C17H10F3N3O3S2
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|---|---|
| Molecular Weight |
425.404811382294
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| Exact Mass |
425.011
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| Elemental Analysis |
C, 48.00 H, 2.37 F, 13.40 N, 9.88 O, 11.28 S, 15.07
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| CAS # |
2170729-29-8
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| PubChem CID |
132260161
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| Appearance |
White to off-white solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
690
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ORQGHAJIWGGFJK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H10F3N3O3S2/c18-17(19,20)8-1-2-13-12(3-8)21-14(28-13)5-23-16(26)10-7-27-6-9(10)11(22-23)4-15(24)25/h1-3,6-7H,4-5H2,(H,24,25)
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| Chemical Name |
2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid
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| Synonyms |
AT-007 AT 007 AT007
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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 : ~35.71 mg/mL (~83.94 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.25 mg/mL (5.29 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 22.5 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. Solubility in Formulation 2: ≥ 2.25 mg/mL (5.29 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 22.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3507 mL | 11.7536 mL | 23.5073 mL | |
| 5 mM | 0.4701 mL | 2.3507 mL | 4.7015 mL | |
| 10 mM | 0.2351 mL | 1.1754 mL | 2.3507 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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