GBT-440

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. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.

Product information

CAS Number: 1446321-46-5

Molecular Weight: 337.37

Formula: C19H19N3O3

Synonym:

Voxelotor

GTx-011

Oxbryta

GBT-440

GBT 440

GBT440

GTx011

GTx 011

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

Smiles: CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=CC(O)=C1C=O

InChiKey: FWCVZAQENIZVMY-UHFFFAOYSA-N

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

Technical Data

Appearance: Solid Power.

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

Solubility: Soluble in DMSO

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

Voxelotor (GBT440) binds to the N-terminal a chain of haemoglobin (Hb), increases haemoglobin S (HbS) affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of red blood cells (RBCs).

In Vivo:

Voxelotor (GBT440; 100-150 mg/kg; administered twice a day by oral gavage for 9-12 days) reduces ex vivo sickling and prolongs red blood cells (RBCs) half-life in a murine model of sickle cell disease (SCD). Voxelotor shows T1/2s of 11.7, 19.1±1.5, 66.0±11, 28.8±4.0 hours for mouse (70 mg/kg; i.v.), rat (1.6 mg/kg; i.v.), dog (1 mg/kg; i.v.), and momkey (1 mg/kg; i.v.), respectively. Voxelotor shows Cmaxs of 81.9, 71.2±6.0, 5.56±1.6, and 25.2±5.5 μg/mL for mouse (30 mg/kg; p.o.), rat (7.2 mg/kg; p.o.), dog (2.5 mg/kg; p.o.), and momkey (4.25 mg/kg; p.o.), respectively.

References:

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.

Products are for research use only. Not for human use.