Migalastat (GR181413A) hydrochloride
(Synonyms: 脱氧半乳糖野生霉素盐酸盐,GR181413A) 目录号 : GC10430
Migalastat (GR181413A) hydrochloride是一种口服的α-半乳糖苷酶A竞争性抑制剂，IC50值为0.04µM。
Cas No.:75172-81-5
Sample solution is provided at 25 µL, 10mM.
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Migalastat (GR181413A) hydrochloride an orally competitive inhibitor of α-galactosidase A, with an IC50 value of 0.04µM[1]. Migalastat hydrochloride targets the mutated form of α-galactosidase A via competitively binding to the enzyme, promoting the transport of the abnormal α-galactosidase A mutant to the lysosome and enhances the activity of enzyme processing globotriaosylceramide (GL-3)[2]. Migalastat hydrochloride has been widely used to increase the level of active α-galactosidase A, and has been employed in the development of new combined therapies[3].
In vitro, Migalastat hydrochloride (1000μM) combined with rhα-galactosidase A (0.5nM) and Fabry patient-derived fibroblasts incubated for 5 hours can increase the intracellular level and activity of α-galactosidase A, and reduce the GL-3 level[4].
In vivo, Migalastat hydrochloride treatment via oral administration at a dose of 100mg/kg/day for 28 days resulted in significant reductions in globotriaosylsphingosine (Lyso-Gb3) levels in kidney, heart, and skin of hR301Q α-Gal A Tg/KO mice[5]. Daily oral administration of 300 mg/kg Migalastat hydrochloride (for 4 weeks) significantly increased the α-galactosidase A activity in hR301Q α-Gal A Tg/KO mice and decreased the GL-3 level[6].
References:
[1] Lenders M, Menke E R, Brand E. Biochemical Amenability in Fabry Patients Under Chaperone Therapy—How and When to Test? M. Lenders et al[J]. BioDrugs, 2024, 38(6): 845-854.
[2] Giugliani R, Waldek S, Germain D P, et al. A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects[J]. Molecular genetics and metabolism, 2013, 109(1): 86-92.
[3] Warnock D G, Bichet D G, Holida M, et al. Oral migalastat HCl leads to greater systemic exposure and tissue levels of active α-galactosidase A in Fabry patients when co-administered with infused agalsidase[J]. PLoS One, 2015, 10(8): e0134341.
[4] Benjamin E R, Khanna R, Schilling A, et al. Co-administration with the pharmacological chaperone AT1001 increases recombinant human α-galactosidase A tissue uptake and improves substrate reduction in Fabry mice[J]. Molecular Therapy, 2012, 20(4): 717-726.
[5] Young-Gqamana B, Brignol N, Chang H H, et al. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients[J]. PLoS One, 2013, 8(3): e57631.
[6] Khanna R, Soska R, Lun Y, et al. The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease[J]. Molecular Therapy, 2010, 18(1): 23-33.
Migalastat (GR181413A) hydrochloride是一种口服的α-半乳糖苷酶A竞争性抑制剂，IC50值为0.04µM[1]。Migalastat hydrochloride通过竞争性结合突变型α-半乳糖苷酶A，促进异常酶蛋白向溶酶体的转运，并增强分解globotriaosylceramide (GL-3)的活性[2]。Migalastat hydrochloride已广泛应用于提升α-半乳糖苷酶A活性水平，并用于开发新型联合疗法[3]。
在体外，将1000µM的Migalastat hydrochloride与rhα-半乳糖苷酶A（0.5nM）共同孵育Fabry患者来源的成纤维细胞5小时，能提高细胞内α-半乳糖苷酶A的含量与活性，并降低GL-3水平[4]。
在体内，每日口服100mg/kg/day剂量的Migalastat hydrochloride持续28天，可显著降低hR301Q α-Gal A Tg/KO小鼠肾脏、心脏和皮肤中的globotriaosylsphingosine (Lyso-Gb3)浓度[5]。每日口服300mg/kg剂量的Migalastat hydrochloride连续4周，能显著提高hR301Q α-Gal A Tg/KO小鼠的α-半乳糖苷酶A活性，并降低GL-3水平[6]。
| Cell experiment [1]: | |
Cell lines | Fabry patient-derived fibroblasts |
Preparation Method | Fabry patient-derived fibroblasts were seeded at a density of 1×106 cells per T-75 culture flask in the growth medium (Dulbecco modified Eagle medium+15% fetal bovine serum) and cultured overnight at 37°C and 8% CO2. The cells were then seeded at a density of 10,000 cells per well in a sterile, transparent-bottom 96-well black culture plate and cultured for 1-2 hours at 37°C and 8% CO2. Subsequently, the cells were incubated separately with rhα-galactosidase A (0.5nM) or together with rhα-galactosidase A (0.5nM) and Migalastat hydrochloride (0.1, 1, 10, 100, and 1000µM) for 5 hours. The cells were washed three times with the culture medium and then cultured in the medium for 2 days. Afterwards, the cells were washed twice with phosphate buffer and lysed for 5 minutes in 35µl of 0.2% Triton X-100, 27mM citric acid monohydrate, and 46mM phosphate buffer (pH 4.6) to detect the activity of α-galactosidase A. |
Reaction Conditions | 0.1, 1, 10, 100, and 1000µM; 5h |
Applications | Migalastat hydrochloride/rhα-galactosidase A coincubation enhanced the α-galactosidase A levels and activity in Fabry fibroblasts in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | hR301Q α-Gal A Tg/KO mice |
Preparation Method | The hR301Q α-Gal A Tg/KO mice were raised in a standard sterile environment and were allowed to freely consume Migalastat hydrochloride (100mg/kg) in the drinking water once daily for 28 days. The mice were then euthanized by carbon dioxide inhalation. Whole blood was collected from the inferior vena cava into lithium heparin anticoagulant tubes and centrifuged at 2700g for 10 minutes at 4°C to separate the plasma. The heart, kidneys, brain and skin (after shaving and removal from the ventral side below the neck) were quickly extracted, rinsed with cold phosphate-buffered saline (PBS), dried, and analyzed. |
Dosage form | 100mg/kg/day for 28 days; p.o. |
Applications | Migalastat hydrochloride administration resulted in significant reductions in Lyso-Gb3 levels in kidney, heart, and skin of mice. |
References: | |
| Cas No. | 75172-81-5 | SDF | |
| 别名 | 脱氧半乳糖野生霉素盐酸盐,GR181413A | ||
| 化学名 | (2R,3S,4R,5S)-2-(hydroxymethyl)-3,4,5-piperidinetriol, monohydrochloride | ||
| Canonical SMILES | O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)NC1.Cl | ||
| 分子式 | C6H13NO4 • HCl | 分子量 | 199.6 |
| 溶解度 | ≤10mg/ml in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 5.01 mL | 25.0501 mL | 50.1002 mL |
| 5 mM | 1.002 mL | 5.01 mL | 10.02 mL |
| 10 mM | 501 μL | 2.505 mL | 5.01 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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Quality Control & SDS
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- Purity: >99.50%
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