75172-81-5 Usage
Description
Deoxygalactonojirimycin hydrochloride, also known as migalastat, is a white crystalline solid that functions as a molecular chaperone to the enzyme α-galactosidase A (α-GAL A). It is used to treat Fabry disease, a condition caused by mutations in the α-GAL A enzyme, which leads to the accumulation of the glycosphingolipid globotriaosylceramide (GL3) in various tissues, causing significant health issues. Migalastat engages with the enzyme, enabling it to adopt the proper conformation for efficient breakdown of GL3.
Uses
1. Used in Pharmaceutical Industry:
Deoxygalactonojirimycin hydrochloride is used as a molecular chaperone for α-galactosidase A to treat Fabry disease in adults and adolescents aged 16 or older. It helps in the proper folding of the enzyme, allowing for efficient metabolism of GL3 and reducing its accumulation in tissues.
2. Used in Research and Development:
Deoxygalactonojirimycin hydrochloride is used as an α-D-galactosidase inhibitor in research settings. It is employed to assess the enzymatic activity of α-galactosidase A and study its effects on mRNA levels in human embryonic kidney (HEK) cells and hippocampal neurons.
3. Used in Drug Development:
Deoxygalactonojirimycin hydrochloride has been developed as a pharmaceutical compound, marketed by Amicus Therapeutics, and approved in the EU for the treatment of Fabry disease. This approval represents an important advance for patients suffering from this disorder, as it provides an alternative to the standard enzyme replacement therapy (ERT) used prior to 2016.
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’s 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.
target
α-galactosidase
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.
Check Digit Verification of cas no
The CAS Registry Mumber 75172-81-5 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,5,1,7 and 2 respectively; the second part has 2 digits, 8 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 75172-81:
(7*7)+(6*5)+(5*1)+(4*7)+(3*2)+(2*8)+(1*1)=135
135 % 10 = 5
So 75172-81-5 is a valid CAS Registry Number.
InChI:InChI=1/C6H13NO4.ClH/c8-2-3-5(10)6(11)4(9)1-7-3;/h3-11H,1-2H2;1H/t3-,4-,5+,6-;/m0./s1
75172-81-5Relevant articles and documents
Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-l-bulgecinine from d-glucuronolactone and of l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine from l-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas l-DMDP is a potent and specific inhibitor of α-glucosidases
Best, Daniel,Wang, Chen,Weymouth-Wilson, Alexander C.,Clarkson, Robert A.,Wilson, Francis X.,Nash, Robert J.,Miyauchi, Saori,Kato, Atsushi,Fleet, George W.J.
experimental part, p. 311 - 319 (2010/05/18)
A convenient large-scale synthesis of 1-deoxynojirimyin (DNJ) from d-glucuronolactone involves introduction of azide at C-5 with retention of configuration to give 5-azido-5-deoxy-1,2-O-isopropylidene-α-d-glucofuranose as a key intermediate in an overall yield of up to 72%; the same intermediate can be transformed into DMDP [(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol] and (3R)-3-hydroxy-l-bulgecinine [(2S,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-l-proline]. l-Glucuronolactone, a readily available l-sugar chiron, may similarly be used to access the enantiomers l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine. A comparison of glycosidase inhibition by DMDP (an inhibitor of β-glucosidases and β-galactosidases) and l-DMDP (a potent and specific α-glucosidase inhibitor) with the corresponding enantiomeric hydroxybulgecinines is reported; DMDP and (3R)-3-hydroxy-l-bulgecinine show weak inhibition of glycogen phosphorylase.
