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Voxelotor

Synonyms: GBT440, GTx011

Voxelotor is a novel small molecule hemoglobin modifier which increases hemoglobin oxygen affinity.

Voxelotor Chemical Structure

Voxelotor Chemical Structure

CAS No. 1446321-46-5

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Biological Activity

Description Voxelotor is a novel small molecule hemoglobin modifier which increases hemoglobin oxygen affinity.
In vitro
In vitro GBT440 is a new potent allosteric effector of sickle cell hemoglobin that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. GBT440 inhibits these isozymes(CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4) with IC50 ranging from 7.9 to 148 μM. It is not a substrate for either P-gp or BCRP transporters[1]. It binds to the N-terminal a chain of Hb[2].
Cell Research Cell lines sickle RBCs
Concentrations 0, 300, 600, 1000 μM
Incubation Time 1 h
Method

whole blood (20% Hct) from SCD patients who has been transfusion free for 2 to 3 months (HbS > 70%) is incubated with various concentrations of GBT440 for 1 h at 37°C, diluted 100-fold in TES/saline buffer and deoxygenated in a Hemox Analyser
In Vivo
In vivo GBT440 has favorable oral bioavailability of 60, 37, and 36% in rats, dogs, and monkeys, respectively, with similar blood and plasma half-lives of approximately 20 h each. T1/2 value of GBT440 in all animal species is significantly shorter than the T1/2 of red blood cells (∼20 days), which supports that binding of GBT440 to hemoglobin is a reversible process. GBT440 is currently in Phase 3 clinical trials (NCT03036813) in SCD patients[1]. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. In a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. GBT440 shows dose proportional PK, a terminal half-life of 1.5-3 d[2].
Animal Research Animal Models Sprague-Dawley rats
Dosages 7.2 to 120 mg/kg
Administration oral administration
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT06023199 Recruiting
Sickle Cell Disease
Inova Health Care Services|Pfizer
 October 23 2023 Phase 2
NCT05289570 Terminated
Acute Lung Injury|End Stage Lung Disease
Duke University
 May 3 2022 Phase 2
NCT05561140 Active not recruiting
Sickle Cell Disease|Leg Ulcers
Pfizer
 May 30 2022 Phase 3
NCT05018728 Recruiting
Sickle Cell Anemia in Children
Amy Tang|Pfizer|Emory University
 March 28 2022 Phase 2
NCT05494541 Completed
Sickle Cell Disease
Novartis Pharmaceuticals|Novartis
 August 30 2021 --

Chemical Information & Solubility

Molecular Weight 337.37 Formula

C19H19N3O3
CAS No. 1446321-46-5 SDF Download Voxelotor SDF
Smiles CC(C)N1C(=CC=N1)C2=C(C=CC=N2)COC3=CC=CC(=C3C=O)O
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 67 mg/mL ( (198.59 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 5 mg/mL

Water : Insoluble


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In vivo
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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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