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| Targets |
URAT1 inhibitor 8 specifically targets the urate transporter 1 (URAT1), a major transporter responsible for uric acid reabsorption in the proximal tubule of the kidney. URAT1 is the primary transporter for renal urate handling and is a validated therapeutic target for gout and hyperuricemia. This compound acts as a URAT1 antagonist (inhibitor) with an IC50 of 0.001 microM (1 nM).
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| ln Vitro |
In cell-free enzyme inhibition assays (or cell-based [14C]-urate uptake assays), URAT1 inhibitor 8 is a potent URAT1 inhibitor, with an IC50 of 0.001 microM. This indicates picomolar affinity and extremely high potency for blocking URAT1-mediated uric acid transport. The compound serves as a highly potent inhibitor of URAT1, applicable in the study of gout.
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| ln Vivo |
Specific in vivo activity data for URAT1 inhibitor 8 has not been published. Based on its potent in vitro URAT1 inhibition (IC50 = 0.001 microM), it is hypothesized to be highly effective at reducing serum uric acid (sUA) levels in vivo. It could be evaluated in hyperuricemic animal models (e.g., potassium oxonate-induced hyperuricemic mice or rats) to measure sUA reduction and urinary uric acid excretion (UUE).
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| Enzyme Assay |
The specific protocol for URAT1 inhibitor 8 involves an in vitro [14C]-urate uptake assay using URAT1-expressing cells. HEK-293 cells or human renal proximal tubule epithelial cells (RPTEC) stably or transiently expressing human URAT1 are seeded in 24-well plates. After 48 hours, cells are washed with sodium-free buffer (pre-warmed to 37degC). URAT1 inhibitor 8 is serially diluted (0.001-1000 nM) in assay buffer and pre-incubated with the cells for 15 minutes. [14C]-uric acid (50 uM) is then added and the cells are incubated for 30 minutes at 37degC. The reaction is terminated by washing cells three times with ice-cold stop buffer. Cells are lysed with 0.2 N NaOH, and the radioactivity is quantified by liquid scintillation counting. The IC50 of 0.001 microM (1 nM) is calculated from the concentration-response curve.
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| Cell Assay |
For in vitro cellular assays, human renal proximal tubule epithelial cells (RPTEC) are cultured in 24-well plates until confluence. URAT1 inhibitor 8 is added to the cells at concentrations ranging from 0.001-1000 nM for 24 hours. After treatment, the culture medium is removed and replaced with fresh medium containing [14C]-uric acid (50 uM) and varying concentrations of the compound. Cells are incubated for 30 minutes at 37degC. Cells are then washed three times, and the intracellular radioactivity is measured to assess uric acid uptake inhibition. The IC50 is calculated from the dose-response curve. Cell viability is assessed using the MTT assay to ensure that the inhibition is not due to cytotoxicity.
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| Animal Protocol |
An in vivo protocol for URAT1 inhibitor 8 would involve a potassium oxonate-induced hyperuricemic mouse model. Male ICR mice (6-8 weeks old, 20-25 g) are fasted overnight with free access to water. Hyperuricemia is induced by intraperitoneal injection of potassium oxonate (250 mg/kg). URAT1 inhibitor 8 is formulated in 0.5% methylcellulose (or 5% DMSO/95% saline) and administered orally by gavage at doses of 0.1, 0.3, 1, 3, and 10 mg/kg, 30 minutes after potassium oxonate injection. Blood samples are collected from the retro-orbital sinus at 0, 1, 2, 4, 6, and 8 hours post-administration. Serum uric acid (sUA) levels are measured using a uric acid assay kit. Urine is collected using metabolic cages to measure urinary uric acid excretion (UUE). The percent reduction in sUA is calculated relative to the hyperuricemic vehicle control.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for URAT1 inhibitor 8 is not available. Based on its chemical structure and potency, the compound is expected to have favorable drug-like properties. For in vivo studies, the compound is formulated in DMSO (100 mg/mL stock) for in vitro experiments and in 0.5% methylcellulose or 5% DMSO/95% saline for in vivo oral administration. Standard PK studies would involve oral administration to mice or rats at 1-10 mg/kg, followed by serial blood sampling and LC-MS/MS analysis to determine T1/2, Cmax, AUC, and oral bioavailability.
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| Toxicity/Toxicokinetics |
Specific toxicology data for URAT1 inhibitor 8 is not available. As a URAT1 inhibitor, the primary safety concern is the potential for increased urinary uric acid excretion, which may lead to the formation of uric acid stones (urolithiasis) in the urinary tract. Other potential adverse effects may include gastrointestinal disturbances (diarrhea, nausea), headache, and rash. Standard toxicity assessment would include acute and repeat-dose toxicity studies in rodents to evaluate target organ toxicity and to determine the maximum tolerated dose (MTD).
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| References | |
| Additional Infomation |
URAT1 inhibitor 8 is a research-grade chemical and is not approved for human clinical use. Its molecular formula is C19H13ClFN3O4S with a molecular weight of 433.84 and a purity of ≥98%. It is a potent, highly selective urate transporter 1 (URAT1) inhibitor with an IC50 of 0.001 microM (1 nM), making it one of the most potent URAT1 inhibitors reported to date. The compound is stored as a powder at -20degC and is soluble in DMSO (100 mg/mL). URAT1 inhibitor 8 may be used for gout research and serves as a valuable tool compound for URAT1-targeted drug discovery.
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| Molecular Formula |
C19H13CLFN3O4S
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| Molecular Weight |
433.840625524521
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| Exact Mass |
433.029
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| CAS # |
1632005-33-4
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| PubChem CID |
86271138
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| Appearance |
White to off-white solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
697
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=C(C=C1OC2=C(C=C(C=C2)S(=O)(=O)NC3=NC=C(C=C3)F)C#N)Cl)CO
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| InChi Key |
LSWMNYFPGSRIIB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H13ClFN3O4S/c20-17-8-15(3-1-12(17)11-25)28-18-5-4-16(7-13(18)9-22)29(26,27)24-19-6-2-14(21)10-23-19/h1-8,10,25H,11H2,(H,23,24)
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| Chemical Name |
4-[3-chloro-4-(hydroxymethyl)phenoxy]-3-cyano-N-(5-fluoropyridin-2-yl)benzenesulfonamide
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3050 mL | 11.5250 mL | 23.0500 mL | |
| 5 mM | 0.4610 mL | 2.3050 mL | 4.6100 mL | |
| 10 mM | 0.2305 mL | 1.1525 mL | 2.3050 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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