Voxelotor
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MedKoo CAT#: 329516

CAS#: 1446321-46-5

Description: Voxelotor, also known as GBT-440, is a hemoglobin S allosteric modulator. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.


Chemical Structure

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Voxelotor
CAS# 1446321-46-5

Theoretical Analysis

MedKoo Cat#: 329516
Name: Voxelotor
CAS#: 1446321-46-5
Chemical Formula: C19H19N3O3
Exact Mass: 337.1426
Molecular Weight: 337.379
Elemental Analysis: C, 67.64; H, 5.68; N, 12.46; O, 14.23

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1350.0 Ready to ship
500.0mg USD 2650.0 Ready to ship
1.0g USD 3850.0 2 weeks
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Synonym: Voxelotor, GBT-440, GBT 440, GBT440, GTx-011, GTx011, GTx 011; Oxbryta.

IUPAC/Chemical Name: 2-hydroxy-6-({2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl}methoxy)benzaldehyde

InChi Key: FWCVZAQENIZVMY-UHFFFAOYSA-N

InChi Code: InChI=1S/C19H19N3O3/c1-13(2)22-16(8-10-21-22)19-14(5-4-9-20-19)12-25-18-7-3-6-17(24)15(18)11-23/h3-11,13,24H,12H2,1-2H3

SMILES Code: O=CC1=C(OCC2=CC=CN=C2C3=CC=NN3C(C)C)C=CC=C1O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Voxelotor (GBT 440) is an inhibitor of haemoglobin S (HbS) polymerization.
In vitro activity: GBT440 produced a concentration-dependent left shift in the OEC relative to untreated SCT blood in the hypertonic phosphate buffer (Figyre 5A) indicating a dose-dependent increase in Hb-O2 affinity. Most importantly, GBT440 dose-dependently decreased the number of sickled SCT RBCs in hypertonic phosphate buffer with pH 6.9 (Figure 5B). These results indicate that GBT440 inhibits in vitro sickling of SCT RBCs under conditions mimicking extreme hypoxia, dehydration and acidosis. Collectively, these results suggest that GBT440 may inhibit sickling of SCT blood in vivo under conditions that promote sickling such as during strenuous exerecise. Reference: Hematol Rep. 2016 Sep 28; 8(3): 6637. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062624/
In vivo activity: Compared to DMSO treated mice, three weeks of GBT440 significantly increased Hct (Fig. 1) such that the chronic anemia was effectively eliminated (Hct in age-matched C57BL/6 male mice, one of the 5 background strains of Berkeley mice, is 37%; Hct in 1 to 6 month old male and female littermate controls of the Berkeley mice is 42%). Echocardiography demonstrated that three weeks of treatment increased left ventricular ejection fraction (LVEF) and stroke volume index (stroke volume divided by body weight), as well as the pulmonary valve velocity time integral (PV VTI) (Fig. 2). Reference: J Biomech Eng. 2021 Mar 1;143(3):034501. https://pubmed.ncbi.nlm.nih.gov/33175151/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 66.67 197.61
DMSO:PBS (pH 7.2) (1:5) 0.16 0.47
DMF 33.0 97.81
Ethanol 43.5 128.94

Preparing Stock Solutions

The following data is based on the product molecular weight 337.379 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Metcalf B, Chuang C, Dufu K, Patel MP, Silva-Garcia A, Johnson C, Lu Q, Partridge JR, Patskovska L, Patskovsky Y, Almo SC, Jacobson MP, Hua L, Xu Q, Gwaltney SL 2nd, Yee C, Harris J, Morgan BP, James J, Xu D, Hutchaleelaha A, Paulvannan K, Oksenberg D, Li Z. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett. 2017 Jan 23;8(3):321-326. doi: 10.1021/acsmedchemlett.6b00491. PMID: 28337324; PMCID: PMC5346980. 2. Dufu K, Lehrer-Graiwer J, Ramos E, Oksenberg D. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. Hematol Rep. 2016 Sep 28;8(3):6637. doi: 10.4081/hr.2016.6637. PMID: 27757216; PMCID: PMC5062624. 3. Gassner R, Schreier D, Hacker T, Tabima DM, Chesler N. GBT440 Increases Hematocrit and Improves Biventricular Function in Berkeley Sickle Cell Disease Mice. J Biomech Eng. 2021 Mar 1;143(3):034501. doi: 10.1115/1.4049079. PMID: 33175151; PMCID: PMC7871994. 4. Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, Silva-Garcia A, Zhou C, Hutchaleelaha A, Patskovska L, Patskovsky Y, Almo SC, Sinha U, Metcalf BW, Archer DR. 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. doi: 10.1111/bjh.14214. Epub 2016 Jul 5. PMID: 27378309.
In vitro protocol: 1. Metcalf B, Chuang C, Dufu K, Patel MP, Silva-Garcia A, Johnson C, Lu Q, Partridge JR, Patskovska L, Patskovsky Y, Almo SC, Jacobson MP, Hua L, Xu Q, Gwaltney SL 2nd, Yee C, Harris J, Morgan BP, James J, Xu D, Hutchaleelaha A, Paulvannan K, Oksenberg D, Li Z. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett. 2017 Jan 23;8(3):321-326. doi: 10.1021/acsmedchemlett.6b00491. PMID: 28337324; PMCID: PMC5346980. 2. Dufu K, Lehrer-Graiwer J, Ramos E, Oksenberg D. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. Hematol Rep. 2016 Sep 28;8(3):6637. doi: 10.4081/hr.2016.6637. PMID: 27757216; PMCID: PMC5062624.
In vivo protocol: 1. Gassner R, Schreier D, Hacker T, Tabima DM, Chesler N. GBT440 Increases Hematocrit and Improves Biventricular Function in Berkeley Sickle Cell Disease Mice. J Biomech Eng. 2021 Mar 1;143(3):034501. doi: 10.1115/1.4049079. PMID: 33175151; PMCID: PMC7871994. 2. Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, Silva-Garcia A, Zhou C, Hutchaleelaha A, Patskovska L, Patskovsky Y, Almo SC, Sinha U, Metcalf BW, Archer DR. 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. doi: 10.1111/bjh.14214. Epub 2016 Jul 5. PMID: 27378309.

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1: Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk VR, Kanter J, Abboud MR, Lehrer-Graiwer J, Tonda M, Intondi A, Tong B, Howard J; HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8;381(6):509-519. doi: 10.1056/NEJMoa1903212. Epub 2019 Jun 14. PubMed PMID: 31199090.

2: Hutchaleelaha A, Patel M, Washington C, Siu V, Allen E, Oksenberg D, Gretler DD, Mant T, Lehrer-Graiwer J. Pharmacokinetics and pharmacodynamics of voxelotor (GBT440) in healthy adults and patients with sickle cell disease. Br J Clin Pharmacol. 2019 Jun;85(6):1290-1302. doi: 10.1111/bcp.13896. Epub 2019 Mar 31. PubMed PMID: 30743314; PubMed Central PMCID: PMC6533444.

3: Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, Mant T, Gretler DD, Dufu K, Hutchaleelaha A, Patel M, Siu V, Dixon S, Landsman N, Tonda M, Lehrer-Graiwer J. A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Blood. 2019 Apr 25;133(17):1865-1875. doi: 10.1182/blood-2018-08-868893. Epub 2019 Jan 17. PubMed PMID: 30655275; PubMed Central PMCID: PMC6484388.

4: Shet AS, Mendelsohn L, Harper J, Ostrowski D, Henry ER, Gwaabe E, Nichols J, Alayash AI, Eaton WA, Thein SL. Voxelotor treatment of a patient with sickle cell disease and very severe anemia. Am J Hematol. 2019 Apr;94(4):E88-E90. doi: 10.1002/ajh.25389. Epub 2019 Jan 8. PubMed PMID: 30592074; PubMed Central PMCID: PMC6408257.

5: Telfer P, Agodoa I, Fox KM, Burke L, Mant T, Jurek M, Tonda M, Lehrer-Graiwer J. Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease. Hematol Rep. 2018 May 22;10(2):7643. doi: 10.4081/hr.2018.7643. eCollection 2018 May 14. PubMed PMID: 30046415; PubMed Central PMCID: PMC6036983.

6: Blyden G, Bridges KR, Bronte L. Case series of patients with severe sickle cell disease treated with voxelotor (GBT440) by compassionate access. Am J Hematol. 2018 May 12. doi: 10.1002/ajh.25139. [Epub ahead of print] PubMed PMID: 29752824.

7: Rutherford NJ, Thoren KL, Shajani-Yi Z, Colby JM. Voxelotor (GBT440) produces interference in measurements of hemoglobin S. Clin Chim Acta. 2018 Jul;482:57-59. doi: 10.1016/j.cca.2018.03.032. Epub 2018 Mar 27. PubMed PMID: 29601794.

8: Estepp JH. Voxelotor (GBT440), a first-in-class hemoglobin oxygen-affinity modulator, has promising and reassuring preclinical and clinical data. Am J Hematol. 2018 Mar;93(3):326-329. doi: 10.1002/ajh.25042. PubMed PMID: 29352729.