Voxelotor(GBT-440 Oxbryta)

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本产品不向个人销售，仅用作科学研究，不用于任何人体实验及非科研性质的动物实验。

CAS NO:	1446321-46-5
规格:	≥98%

包装与价格：

包装	价格(元)
5mg	电议
10mg	电议
25mg	电议
50mg	电议
100mg	电议
250mg	电议
500mg	电议

产品介绍

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.

理化性质和储存条件

Molecular Weight (MW)	337.37
Formula	C19H19N3O3
CAS No.	1446321-46-5
Storage	-20℃ for 3 years in powder form
Storage	-80℃ for 2 years in solvent
Solubility (In vitro)	DMSO: 67 mg/mL (198.59 mM)
	Water: <1 mg/mL
	Ethanol:67 mg/mL (198.59 mM)
Solubility (In vivo)	O=CC1=C(OCC2=CC=CN=C2C3=CC=NN3C(C)C)C=CC=C1O
Synonyms	GBT-440, GBT 440, GBT440; GTx-011, GTx011, GTx 011; Voxelotor; Oxbryta

实验参考方法

In Vitro	In vitro activity: GBT440 binds to the N-terminal a chain of Hb. it 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. Kinase Assay: Voxelotor (formerly known as GBT-440) is a potent and orally active 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. Cell Assay: 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	BT440 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. 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.
Animal model	Sprague-Dawley rats
Formulation & Dosage	7.2 to 120 mg/kg;oral administration.
References	ACS Med Chem Lett. 2017 Jan 23;8(3):321-326;Br J Haematol. 2016 Oct;175(1):141-53