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Purity: ≥98%
Voxelotor (formerly known as GBT-440; trade name: Oxbryta) is a potent and orally bioactive allosteric effector of sickle cell hemoglobin. It increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, Voxelotor binds with a 1:1 stoichiometry. Voxelotor is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. In November 2019, voxelotor received accelerated approval in the United States for the treatment of sickle cell disease (SCD) for those 12 years of age and older. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
| ln Vitro |
Red blood cell (RBC) sickling is prevented by voxelotor (GBT440), which binds to the N-terminal hemoglobin (Hb) chain and increases hemoglobin S's (HbS's) affinity for oxygen [1]. It also delays HbS polymerization in vitro.
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| ln Vivo |
Voxelotor (GBT440; 100–150 mg/kg; given twice daily by oral gavage for 9–12 days) prolongs the half-life of red blood cells (RBCs) and decreases isolated sickle cell [1]. In mice (70 mg/kg; IV), rats (1.6 mg/kg; IV), dogs (1 mg/kg; IV), and momkeys (1 mg/kg; IV), voxelotor revealed T1/2 values of 11.7, 19.1±1.5, 66.0±11, and 28.8±4.0 hours, respectively [1]. For mice (30 mg/kg; po), rats (7.2 mg/kg; po), dogs (2.5 mg/kg; po), and momkeys (4.25 mg/kg; po), voxelotor has Cmaxs of 81.9, 71.2±6.0, 5.56±1.6, and 25.2±5.5 μg/mL[1].
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| Animal Protocol |
Animal/Disease Models: HbSS Townes knock-in sickle mice (SS mice)[1]
Doses: 100 and 150 mg/kg Route of Administration: Oral administration; twice a day; for 9-12 days Experimental Results: decreased haemolysis. Animal/Disease Models: C57BL/6J mice, SD (Sprague-Dawley) rats, Beagle dogs and Cynomolgus monkeys[1] Doses: 70, 1.6, 1 and 1 mg/kg for mice, rats, dogs and monkeys, respectively 30, 7.2, 2.5 and 4.25 mg/kg for mice, rats, dogs and monkeys, respectively Route of Administration: intravenous (iv) (IV: 70, 1 6, 1 and 1 mg/kg, respectively) Oral (PO: 30, 7 2, 2 5 and 4 3 mg/kg, respectively) Experimental Results: T1 /2s of 11.7, 19.1±1.5, 66.0±11, 28.8±4.0 hrs (hours) for mouse (70 mg/kg; iv), rat (1.6 mg/kg; iv), dog (1 mg/kg; iv), and momkey (1 mg/kg; iv), respectively. Cmaxs of 81.9, 71.2±6.0, 5.56±1.6, and 25.2±5.5 μg/mL for mouse (30 mg/kg; po), rat (7.2 mg/kg; po) , dog (2.5 mg/kg; po), and momkey (4.25 mg/kg; po), respectively. |
| References |
[1]. Oksenberg D, et al. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Oct;175(1):141-53.
[2]. Metcalf B, Chuang C, Dufu K, et al. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett. 2017;8(3):321-326. |
| Molecular Formula |
C19H19N3O3
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| Molecular Weight |
337.37
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| CAS # |
1446321-46-5
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| Related CAS # |
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| SMILES |
O(C1=C([H])C([H])=C([H])C(=C1C([H])=O)O[H])C([H])([H])C1C([H])=C([H])C([H])=NC=1C1=C([H])C([H])=NN1C([H])(C([H])([H])[H])C([H])([H])[H]
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| Synonyms |
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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 (7.41 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 (7.41 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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: ≥ 2.08 mg/mL (6.17 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (6.17 mM) 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 20.8 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 5: ≥ 2.08 mg/mL (6.17 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 6: 0.5 mg/mL (1.48 mM) in 1% DMSO + 99% Saline (add these co-solvents sequentially from left to right, and one by one),clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9641 mL | 14.8205 mL | 29.6410 mL | |
| 5 mM | 0.5928 mL | 2.9641 mL | 5.9282 mL | |
| 10 mM | 0.2964 mL | 1.4821 mL | 2.9641 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.
 Time-dependent change in hemoglobin-oxygen affinity for1,4, and5. Measurement was taken after a 20 min oxygenation/deoxygenation cycle in the Hemox Analyzer.ACS Med Chem Lett. 2017 Jan 23;8(3):321-326. |
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 Cocrystal structure of6(in stick) with CO-ligand HbS.ACS Med Chem Lett. 2017 Jan 23;8(3):321-326. |
 Zoomed image of the binding pocket for31. The H-bond with Ser131 from the neighboring α chain appears to be a key interaction for maintaining the R-state of HbS.ACS Med Chem Lett. 2017 Jan 23;8(3):321-326. |
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