Deoxygalactonojirimycin Hydrochloride

Description

Migalastat, which is marketed by Amicus Therapeutics, received approval in the EU for the treatment of Fabry disease in adults and adolescents aged 16 or older. Fabry disease is caused by mutations of the enzyme α-galactosidase A (α-GAL A) that cause protein misfolding and prevents efficient metabolism of the glycosphingolipid globotriaosylceramide (GL3). Accumulation of GL3 in lysosomes, blood vessels, and various tissues ultimately leads to significant heart, kidney, and dermatological problems. Migalastat functions as a molecular chaperone to α- GAL A, engaging the enzyme and enabling it to adopt the proper conformation allowing for efficient breakdown of GL3. Because the standard of care prior to 2016 for treating Fabry disease was enzyme replacement therapy (ERT), migalastat’s approval in the EU represents an important advance for patients suffering from this disorder.

Chemical properties

White Crystalline Solid

The Uses of Deoxygalactonojirimycin Hydrochloride

Proven to be an extremely potent and selective a-D-galactosidase inhibitor.

The Uses of Deoxygalactonojirimycin Hydrochloride

inhibitor of b-glucosidase

The Uses of Deoxygalactonojirimycin Hydrochloride

Deoxygalactonojirimycin hydrochloride has been used as an α-galactosidase A inhibitor to assess the enzymatic activity of α-galactosidase A. It has also been used as an α-galactosidase A inhibitor to study its effects on the mRNA levels in human embryonic kidney (HEK) cells and hippocampal neurons.

What are the applications of Application

Deoxygalactonojirimycin Hydrochloride is a potent and selective a-galactosidase inhibitor

brand name

Treatment of Fabry disease.

Biochem/physiol Actions

Deoxygalactonojirimycin hydrochloride is an inhibitor of α-galactosidase A. Deoxygalactonojirimycin exhibits therapeutic effects against Fabry disease.

Synthesis

Several unique synthetic approaches to migalastat, which is also known as D-1-deoxygalactonojirimycin (DGJ), have been reported in the literature. Although the most likely commercial-scale preparation of this drug proceeds through a microbial fermentation process disclosed in a 2015 patent, a kilogram-scale synthesis of the drug outlined has been described in a 2008 patent application filed by Amicus. This route closely resembles a procedure disclosed in 1999 by Uriel and Santoyo-Gonzalez that presented handling and safety concerns. Commercial D-galactose (143) was treated with five equivalents of pivaloyl imidazole (144), followed by triflation, treatment with Hunig?ˉs base, and exposure to sodium nitrite to furnish the tetrapivaloyl altofuranose triflate 145 after recrystallization from heptane. Next, stereospecific azide displacement of the triflate successfully delivered azidofuranose 146 in 65-70% yield. This reaction generated over 3 kg of the desired alkyl azide after recrystallization from ethanol and water. Lastly, palladium-catalyzed hydrogenolysis in the presence of sodium methoxide, a methanolic acidification step, and then a subsequent acidification step using HCl in THF furnished migalastat hydrochloride (XV) in 70-75% yield over the three-step sequence from 146.

References

[1] asano n, ishii s, kizu h, et al. in vitro inhibition and intracellular enhancement of lysosomal α‐galactosidase a activity in fabry lymphoblasts by 1‐deoxygalactonojirimycin and its derivatives[j]. febs journal, 2000, 267(13): 4179-4186.
[2] ishii s, chang h, yoshioka h, et al. preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for fabry disease[j]. journal of pharmacology and experimental therapeutics, 2009, 328(3): 723-731.