Amigal

Migalastat (GR181413A (free base)) is an orally active and competitive inhibitor of α-galactosidase A (α-Gal A) with an IC50 of 0.04 μM for human α-Gal A[1].

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IC50: 0.04 μM (human α-Gal A)[1]; Ki: 0.04 μM (human α-Gal A)[1]

Both IC50 and Ki values of Migalastat toward human lysosomal a-Gal A are 0.04 μM[1]. Cell Viability Assay[4] Cell Line: EHK cells mutated α-Gal A Concentration: 10 μM Incubation Time: 9 days Result: Reduced Gb3 accumulation and lysosome volume.

Fabry disease is an X-linked recessive disorder caused by the deficient activity of α-galactosidase A[2]. Migalastat (oral gavage, 3 mg/kg daily for 4 weeks) increases α-Gal A activity in heart, kidney, spleen, and liver in a dose- and time-dependently in transgenic mice that express human mutant alpha-Gal A (TgM)[2]. Migalastat shows the half-life of less than 1 day in all major issues in TgM for 2 weeks pretreatment[2]. Migalastat (oral gavage, 100 mg/kg daily for 28 days) to transgenic mice reduces lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively[3]. Animal Model: Male nontransgenic (Non-Tg) C57BL/6 mice; transgenic mice expressing human mutant R301Q α-Gal A (TgM), α-Gal A knockout mice (KO), mice express human R301Q α-Gal A in a null background (TgM/KO)[2] Dosage: 3 mg/kg Administration: Oral gavage; every day for 4 weeks Result: Reduced Globotriaosylceramide (Gb3) storage remarkably in kidney of mice.

[1]. Asano N, et al. In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives. Eur J Biochem. 2000 Jul;267(13):4179-86.

[2]. Ishii S, et al. Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. J Pharmacol Exp Ther. 2009 Mar;328(3):723-31.

[3]. Young-Gqamana B, et al. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PLoS One. 2013;8(3):e57631.

[4]. Welford RWD, et al. Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types. Hum Mol Genet. 2018 Oct. 27(19):3392-3403.