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Voxelotor

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1 US Medicaid Prescriptions, 2 Annual Reports

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1 US Medicaid Prescriptions
2 Annual Reports

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38 US Patents
7 US Exclusivities

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Chemistry

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Also known as: 1446321-46-5, Oxbryta, Gbt440, Gbt 440, Gbt-440, Gtx-011

Molecular Formula

C₁₉H₁₉N₃O₃

Molecular Weight

337.4 g/mol

InChI Key

FWCVZAQENIZVMY-UHFFFAOYSA-N

FDA UNII

3ZO554A4Q8

Voxelotor is an orally bioavailable modulator and stabilizer of sickle cell hemoglobin (HbS), with potential use in the treatment of sickle cell disease (SCD). Upon administration, voxelotor targets and covalently binds to the N-terminal valine of the alpha chain of HbS. This stabilizes HbS, thereby improving oxygen binding affinity. The binding of voxelotor to HbS prevents HbS polymerization, reduces sickling, decreases red blood cell (RBC) damage and increases the half-life of RBCs. This improves blood flow and decreases hemolytic anemia.

1 2D Structure

Voxelotor

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde

2.1.2 InChI

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

2.1.3 InChI Key

FWCVZAQENIZVMY-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC(C)N1C(=CC=N1)C2=C(C=CC=N2)COC3=CC=CC(=C3C=O)O

2.2 Other Identifiers

2.2.1 UNII

3ZO554A4Q8

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-3-pyridinyl)methoxy)benzaldehyde

2. Gbt440

3. Oxbryta

2.3.2 Depositor-Supplied Synonyms

1. 1446321-46-5

2. Oxbryta

3. Gbt440

4. Gbt 440

5. Gbt-440

6. Gtx-011

7. Hemoglobin Modulators-1

8. Voxelotor [usan]

9. 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

10. 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde

11. Chembl4101807

12. 3zo554a4q8

13. Voxelotor (usan)

14. 2-hydroxy-6-({2-[1-(propan-2-yl)-1h-pyrazol-5-yl]pyridin-3-yl}methoxy)benzaldehyde

15. Benzaldehyde, 2-hydroxy-6-((2-(1-(1-methylethyl)-1h-pyrazol-5-yl)-3-pyridinyl)methoxy)-

16. 2-hydroxy-6-((2-(1-(propan-2-yl)-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

17. Oxbryta (tn)

18. Voxelotor [inn]

19. Gbt-440(voxelotor)

20. Voxelotor [mi]

21. Voxelotor [who-dd]

22. Unii-3zo554a4q8

23. Voxelotor [orange Book]

24. Schembl15065529

25. Gtpl10559

26. Voxelotor(gbt440, Gtx011)

27. Dtxsid801027954

28. Bcp20182

29. Ex-a2980

30. Bdbm50235297

31. Zinc145969085

32. Ccg-267884

33. Cs-5317

34. Db14975

35. Sb19656

36. 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-3-pyridinyl)methoxy)benzaldehyde

37. Compound 36 [pmid: 28337324]

38. Ac-36867

39. As-57911

40. Da-44587

41. Hy-18681

42. Ft-0702904

43. S8540

44. D11330

45. Gbt-440;gbt440;voxelotor;gtx-011;gtx011;gtx 011

46. 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy) Benzaldehyde

2.4 Create Date

2013-07-15

3 Chemical and Physical Properties

Molecular Formula	C₁₉H₁₉N₃O₃
Molecular Weight	337.4 g/mol
XLogP3	2.7
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	6
Exact Mass	337.14264148 g/mol
Monoisotopic Mass	337.14264148 g/mol
Topological Polar Surface Area	77.2 Å²
Heavy Atom Count	25
Formal Charge	0
Complexity	434
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Voxelotor is indicated to treat sickle cell disease in both adult and pediatric patients aged 4 years and older.

Oxbryta is indicated for the treatment of haemolytic anaemia due to sickle cell disease (SCD) in adults and paediatric patients 12 years of age and older as monotherapy or in combination with hydroxycarbamide.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Voxelotor modifies hemoglobin to prevent painful and dangerous sickle cell crises that normally lead to organ damage, hospitalization, and sometimes death. It prevents low hemoglobin, which is normally associated with the destruction of sickled blood cells in sickle cell disease. Voxelotor has led to up to a 40% increase in hemoglobin in clinical trials.

5.2 MeSH Pharmacological Classification

Hematologic Agents

Drugs that act on blood and blood-forming organs and those that affect the hemostatic system. (See all compounds classified as Hematologic Agents.)

5.3 ATC Code

B06AX03

B - Blood and blood forming organs

B06 - Other hematological agents

B06A - Other hematological agents

B06AX - Other hematological agents

B06AX03 - Voxelotor

5.4 Absorption, Distribution and Excretion

Absorption

Voxelotor is rapidly absorbed after oral administration, with a plasma Tmax of 2 hours. Tmax in the red blood cells ranges from 17-24 hours. The Cmax, on average in whole blood and red blood cells occur 6 and 18 hours after an oral dose, respectively. Consumption of a high fat meal with voxelotor significantly increased exposure to the drug during clinical trials. After a daily dose of either 300, 600, or 900 mg for a period of 15 days, when steady-state concentrations were reached, the average RBC Cmax for the respective doses were measured to be 4950, 9610 and 14 000 g*h mL1, respectively.

Route of Elimination

62.6% of the voxelotor dose administered orally as well as its metabolites are found in the feces (with 33.3% as unchanged drug) and 35.5% in urine (with only 0.08% unchanged drug).

Volume of Distribution

The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma.

Clearance

The apparent oral clearance of voxelotor is approximately 6.7 L/h.

5.5 Metabolism/Metabolites

Voxeletor is heavily metabolized via 2 phases. Phase I consists of oxidation and reduction, while phase II consists of glucuronidation. Voseletor is oxidized mainly by CYP3A4, and to a lesser extent by CYP2C19, CYP2B6, and CYP2C9 hepatic cytochrome enzymes.

5.6 Biological Half-Life

The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours, according to the FDA label. The mean half-life in the red blood cell is 60 days. The average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 6185 hours in healthy patients, in one clinical study.

5.7 Mechanism of Action

Deoxygenated sickle hemoglobin (HbS) polymerization is the causal factor for sickle cell disease. The genetic mutation associated with this disease leads to the formation of abnormal, sickle shaped red blood cells that aggregate and block blood vessels throughout the body, causing vaso-occlusive crises. Voxelotor binds irreversibly with the Nterminal valine of the chain of hemoglobin, leading to an allosteric modification of Hb20, which increases the affinity for oxygen. Oxygenated HbS does not polymerize. By directly blocking HbS polymerization, voxelotor can successfully treat sickle cell disease by preventing the formation of abnormally shaped cells, which eventually cause lack of oxygenation and blood flow to organs.

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