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Purity: ≥98%
Verinurad (formerly known as RDEA-3170; RDEA3170) is a novel, highly potent and specific URAT1 (Urate transporter 1) inhibitor with anti-hyperuricemic effects. It inhibits URAT1 with an IC50 of 25 nM and is currently under clinical trials for treating gout. High affinity inhibition of uric acid transport requires URAT1 residues Cys-32, Ser-35, Phe-365 and Ile-481. Unlike other available uricosuric agents, the requirement for Cys-32 is unique to verinurad. Two of these residues, Ser-35 and Phe-365, are also important for urate transport kinetics. A URAT1 binding assay using radiolabeled verinurad revealed that distinct URAT1 inhibitors benzbromarone, sulfinpyrazone and probenecid all inhibit verinurad binding via a competitive mechanism. However, mutations made within the predicted transporter substrate channel differentially altered the potency for individual URAT1 inhibitors. Overall, the results suggest that URAT1 inhibitors bind to a common site in the core of the transporter and sterically hinder the transit of uric acid through the substrate channel, albeit with vastly different potencies and with differential interactions with specific URAT1 amino acids.
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| ln Vitro |
With an IC50 of 25 nM, verinurad exhibits strong efficacy and dose-dependent inhibition of human URAT1's transport activity [1].
1. Verinurad (RDEA3170) exhibits high potency and specificity for human URAT1, with no significant inhibitory effect on the transport activity of human OAT4 and OAT1 when tested in cell-based transport assays. In the assay, cells expressing URAT1 were incubated with ^{14}C-uric acid, and cells expressing OAT4 or OAT1 were incubated with carboxyfluorescein in the presence of different concentrations of verinurad [1] 2. High-affinity inhibition of uric acid transport by Verinurad (RDEA3170) is dependent on specific residues of URAT1, namely Cys-32, Ser-35, Phe-365 and Ile-481; the requirement for Cys-32 is unique to verinurad compared with other uricosuric agents, and Ser-35 and Phe-365 are also crucial for urate transport kinetics [1] 3. A binding assay using ^{3}H-verinurad showed that ^{3}H-verinurad binds specifically and saturably to membranes from cells transfected with human URAT1, but not to membranes from cells transfected with empty vector. Unlabeled verinurad, benzbromarone, sulfinpyrazone and probenecid all inhibit the binding of ^{3}H-verinurad to URAT1 in a dose-dependent manner, indicating a competitive inhibition mechanism [1] 4. Mutations in the predicted substrate channel of URAT1 (e.g., F241Y, F449Y, R477K) differentially alter the potency of individual URAT1 inhibitors (verinurad, benzbromarone, sulfinpyrazone, probenecid) for URAT1; for example, the hURAT1-F449Y mutant has the same affinity for verinurad but an 11-fold lower affinity for benzbromarone compared with wild-type human URAT1 [1] 5. Chimeric point mutation experiments of rat and human URAT1 (at positions 35, 365 and 481) demonstrated that Ser-35, Phe-365 and Ile-481 of human URAT1 cooperate to enhance the affinity of verinurad for URAT1; the double point mutant chimera rat URAT1 (r-N35S/F365Y) showed altered urate transport kinetics (K m) compared with wild-type rat URAT1 [1] |
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| ln Vivo |
1. In healthy human volunteers, a single 40 mg dose of Verinurad (RDEA3170) reduced baseline serum uric acid (sUA) levels by up to 60% for a sustained time period [1]
2. Verinurad (RDEA3170) increased the fractional excretion of uric acid (FEUA) in humans in a dose-dependent manner, with a half-maximal effective plasma concentration of 22 nM [1] |
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| Enzyme Assay |
1. URAT1 binding assay with radiolabeled verinurad: Membranes were prepared from cells transfected with human URAT1 or empty vector. The membranes were incubated with different concentrations of ^{3}H-verinurad (in the absence or presence of unlabeled inhibitors) for a specific period. After incubation, the membrane-bound radioactivity was measured to determine the specific binding of ^{3}H-verinurad to URAT1. For competitive inhibition experiments, 10 nM of ^{3}H-verinurad was incubated with URAT1 membranes together with different concentrations of unlabeled verinurad, benzbromarone, sulfinpyrazone or probenecid, and the bound radioactivity was quantified [1]
2. Dose-response binding assay for URAT1 mutants: Membranes were prepared from cells transfected with hURAT1 mutants (e.g., F449Y). The membranes were incubated with 10 nM of ^{3}H-verinurad and different concentrations of unlabeled verinurad or benzbromarone, and the bound radioactivity was measured to analyze the affinity of inhibitors for the mutant URAT1 [1] 3. Eadie-Hofstee linearization analysis for binding kinetics: Membranes containing human URAT1 were incubated with different concentrations of ^{3}H-verinurad in the absence or presence of fixed concentrations of unlabeled inhibitors (20 nM verinurad, 50 nM benzbromarone, 25 µM sulfinpyrazone, 200 µM probenecid). The specifically bound ^{3}H-verinurad was analyzed by Eadie-Hofstee linearization to determine the binding mechanism [1] |
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| Cell Assay |
1. URAT1/OAT transport activity assay: HEK293 cells were transfected with plasmids encoding human URAT1, OAT4 or OAT1. Transfected cells were incubated with ^{14}C-uric acid (for URAT1) or carboxyfluorescein (for OAT4/OAT1) in the presence of serial concentrations of Verinurad (RDEA3170). After incubation, the intracellular radioactivity (for URAT1) or fluorescence intensity (for OAT4/OAT1) was measured to evaluate the transport activity of the transporters, and dose-response curves were generated to calculate the inhibitory potency of verinurad [1]
2. URAT1 mutant transport activity assay: HEK293 cells were transfected with plasmids encoding wild-type human URAT1, rat URAT1, or chimeric point mutants (e.g., hURAT1-F365Y, rURAT1-Y365F, rURAT1-N35S/F365Y). The transport activity of these mutants was assessed using the same ^{14}C-uric acid incubation method as the wild-type URAT1 assay, and the K m (half maximal transport velocity) of urate transport was calculated for each construct [1] 3. Inhibitor potency assay for URAT1 mutants: HEK293 cells expressing hURAT1 mutants (F241Y, F449Y, R477K) were treated with different concentrations of verinurad, benzbromarone, sulfinpyrazone or probenecid. The transport activity of the mutants was measured via ^{14}C-uric acid uptake, and the potency of each inhibitor for the mutants was determined and compared with wild-type hURAT1 [1] |
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| References | ||
| Additional Infomation |
Verinurad has been used in basic science and therapeutic research on gout, gout with hyperuricemia, and gout with asymptomatic hyperuricemia.
1. Verinurad (RDEA3170) is a potent and specific URAT1 inhibitor that is currently being evaluated for its efficacy in treating hyperuricemia and gout[1] 2. All URAT1 inhibitors (including Verinurad, benzbromarone, sulfinpyrazone, and probenecid) bind to a common site in the core of the URAT1 transporter and block the transport of uric acid through substrate channels by steric hindrance, but their potency varies greatly and their interactions with specific amino acids of URAT1 are also different[1] 3. One unique feature of Verinurad (RDEA3170) compared to other marketed inhibitors is that its high-affinity inhibitory effect requires the URAT1 residue Cys-32. Uric acid excretion drugs[1] |
| Molecular Formula |
C20H16N2O2S
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| Molecular Weight |
348.42
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| Exact Mass |
348.093
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| Elemental Analysis |
C, 68.95; H, 4.63; N, 8.04; O, 9.18; S, 9.20
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| CAS # |
1352792-74-5
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| Related CAS # |
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| PubChem CID |
54767229
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
566.7±50.0 °C at 760 mmHg
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| Flash Point |
296.5±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.692
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| LogP |
3.77
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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 |
25
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| Complexity |
541
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)(SC1=C(C2=C3C=CC=CC3=C(C#N)C=C2)C=NC=C1)C(O)=O
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| InChi Key |
YYBOLPLTQDKXPM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H16N2O2S/c1-20(2,19(23)24)25-18-9-10-22-12-17(18)16-8-7-13(11-21)14-5-3-4-6-15(14)16/h3-10,12H,1-2H3,(H,23,24)
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| Chemical Name |
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.18 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (7.18 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 (7.18 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 | 2.8701 mL | 14.3505 mL | 28.7010 mL | |
| 5 mM | 0.5740 mL | 2.8701 mL | 5.7402 mL | |
| 10 mM | 0.2870 mL | 1.4350 mL | 2.8701 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.
 Verinurad is highly potent and specific for human URAT1.Sci Rep.2017 Apr 6;7(1):665. |
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Phe-365 of human URAT1 is important for affinity for verinurad.Sci Rep.2017 Apr 6;7(1):665. |
Human URAT1 Ser-35 and Phe-365 cooperate to enhance urate affinity.Sci Rep.2017 Apr 6;7(1):665. |
 Each URAT1 inhibitor has a distinct profile of potencies for URAT1 mutants.Sci Rep.2017 Apr 6;7(1):665. |
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 A novel URAT1 binding assay replicates the results of inhibition of URAT1 activity.Sci Rep.2017 Apr 6;7(1):665. |
Inhibitors bind to the same binding site on URAT1. |
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