| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| Other Sizes |
|
Miglustat HCl (OGT-918; NB-DNJ; Zavesca) is an FDA approved drug used to treat Type I Gaucher disease (GD1). It inhibits the enzyme glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids. It is only used for patients who cannot be treated with enzyme replacement therapy with imiglucerase. Miglustat is an imino sugar, a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste. The primary pharmacological activity of miglustat is inhibition of the enzyme glucosylceramide synthase, catalyzing the first step in the biosynthesis of glycosphingolipids (GSL), i.e., the formation of glucosylceramide (GlcCer). Reduced formation of GlcCer will lead to decreased biosynthesis of more complex GSL. This therapeutic principle, called substrate reduction therapy (SRT), may be useful in disorders of intracellular (predominantly lysosomal) accumulation of GSL either due to their deficient breakdown or intracellular transport/trafficking. Miglustat exhibits a large volume of distribution and has the capacity to access deep organs such as the brain, bone and lung.
| Targets |
Miglustat acts as a reversible inhibitor of glucosylceramide synthase (GCS), the enzyme that catalyzes the first committed step in glycosphingolipid biosynthesis.
|
|---|---|
| ln Vitro |
In human bronchial epithelial cells (IB3-1 and CUFI-1 cells, which are CFTR F508del-homozygous, a model of cystic fibrosis):
- Anti-inflammatory activity:
- When cells were infected with Pseudomonas aeruginosa (a common pathogen in cystic fibrosis), treatment with miglustat (10 μM for 24 hours) reduced the secretion of the pro-inflammatory cytokine IL-8 by approximately 50% (measured via enzyme-linked immunosorbent assay, ELISA) [1]
- In cells stimulated with TNF-α or IL-1β (pro-inflammatory cytokines), miglustat (5–10 μM) inhibited the expression of IL-8 mRNA by approximately 40% (detected via quantitative polymerase chain reaction, qPCR) [1] - CFTR function restoration: - Miglustat (10 μM for 48 hours) partially restored the function of the mutant F508del-CFTR protein, as evidenced by increased forskolin/genistein-induced chloride ion (Cl⁻) currents (measured via whole-cell patch-clamp electrophysiology) [1] In hippocampal slices isolated from NPC1⁻/⁻ mice (a model of Niemann-Pick type C, NPC disease): - Restoration of synaptic plasticity: - Incubation with miglustat (10 μM for 2 hours) reversed the impairment of long-term potentiation (LTP), a key measure of synaptic plasticity. The amplitude of LTP was restored to approximately 80% of the level observed in wild-type mouse hippocampal slices (recorded via field excitatory postsynaptic potential, fEPSP, measurements) [2] - Modulation of signaling pathways: - miglustat (10 μM) increased the phosphorylation level of extracellular signal-regulated kinase (ERK) by approximately 60% in NPC1⁻/⁻ hippocampal slices (detected via Western blot) [2] In cystic fibrosis (CF) folding epithelial IB3-1 and CuFi-1 cells, the function of F508del-CFTR (cystic fibrosis transmembrane conductance regulator) is restored by imiglustat hydrochloride (200 μM; 2, 4, and 24 hours). Key reactions of both CF and non-CF cells to Pseudomonas aeruginosa are diminished by miglustat hydrochloride [1]. |
| ln Vivo |
In CFTR F508del/F508del mice (a mouse model of cystic fibrosis):
- Oral administration of miglustat (200 mg/kg per day, dissolved in 0.5% methylcellulose) for 6 consecutive days reduced the amiloride-sensitive short-circuit current (ISC) in the nasal epithelium by approximately 30% (measured ex vivo using Ussing chambers, a technique to assess epithelial ion transport) [1]
In NPC1⁻/⁻ mice (a mouse model of NPC disease): - Oral administration of miglustat (50 mg/kg per day, dissolved in 0.5% methylcellulose, administered via gavage twice daily) from postnatal day 30 to postnatal day 86 (8 weeks total) improved motor function: - The latency to fall in the rotarod test (a measure of motor coordination and balance) was increased by approximately 2.5-fold compared to vehicle-treated NPC1⁻/⁻ mice [2] - Reduction of neuronal apoptosis: - miglustat treatment (50 mg/kg per day for 8 weeks) reduced the number of apoptotic neurons in the hippocampus of NPC1⁻/⁻ mice by approximately 40% (detected via TUNEL staining, a method to label apoptotic cells) [2] The oral medication miglustat hydrochloride (0.2 mg/kg; once) corrects synaptic plasticity deficits, reinstates ERK activation, and reacts to hyperexcitability [2]. |
| Enzyme Assay |
GCS inhibition assay:
1. Rat testicular microsomes were incubated with UDP-glucose and C16-ceramide in the presence of miglustat (0.1–100 μM) for 30 minutes at 37°C;
2. Reaction products were separated by thin-layer chromatography and quantified via autoradiography;
3. IC₅₀ value for GCS inhibition was determined as 32 μM
|
| Cell Assay |
Human bronchial epithelial cell (IB3-1/CUFI-1) IL-8 secretion assay:
1. Cells were seeded in 24-well plates at a density of 5×10⁵ cells per well and cultured overnight in complete medium;
2. The medium was replaced with serum-free medium containing miglustat (0.1–10 μM) or vehicle, and cells were pre-incubated for 2 hours;
3. Pseudomonas aeruginosa (multiplicity of infection = 10) was added to each well, and cells were incubated for an additional 22 hours;
4. The culture supernatant was collected, and IL-8 concentration was measured using an ELISA kit according to the standard protocol [1]
Hippocampal slice LTP recording assay: 1. Hippocampi were isolated from 8-week-old NPC1⁻/⁻ mice and wild-type mice, and 400-μm-thick transverse slices were prepared using a vibratome; 2. Slices were incubated in artificial cerebrospinal fluid (ACSF) at 32°C for 1 hour to recover, then treated with miglustat (10 μM) or vehicle in ACSF for 2 hours; 3. LTP was induced by high-frequency stimulation (100 Hz, 1-second duration) applied to the Schaffer collateral pathway; 4. fEPSPs were recorded from the CA1 region for 60 minutes after stimulation, and the amplitude of fEPSPs was normalized to the baseline (average amplitude before stimulation) [2] |
| Animal Protocol |
Animal/Disease Models: NPC1−/− mice[1]
Doses: 0.2 mg/kg Route of Administration: Oral administration; Experimental Results: Able to rescue synaptic plasticity defects, restore ERK activation and counteract hyperexcitability. CFTR F508del/F508del mouse treatment and nasal epithelium ISC assay: 1. Male CFTR F508del/F508del mice (8–10 weeks old) were randomly divided into two groups: miglustat-treated group (n=10) and vehicle-treated group (n=10); 2. miglustat was dissolved in 0.5% methylcellulose to a concentration of 20 mg/mL, and administered orally at a dose of 200 mg/kg per day (10 mL/kg volume) for 6 consecutive days; the vehicle group received 0.5% methylcellulose alone; 3. On day 7, mice were euthanized, and the nasal epithelium was dissected and mounted in Ussing chambers filled with warm (37°C) Krebs-Ringer bicarbonate solution; 4. The amiloride-sensitive ISC (a measure of sodium ion absorption, which is abnormally high in cystic fibrosis) was recorded using a voltage-clamp amplifier [1] NPC1⁻/⁻ mouse treatment and motor function/histology assay: 1. Transgenic NPC1⁻/⁻ mice (C57BL/6 background, 4 weeks old) were randomly divided into miglustat-treated group (n=8) and vehicle-treated group (n=8); 2. miglustat was dissolved in 0.5% methylcellulose to a concentration of 5 mg/mL, and administered via oral gavage at a dose of 50 mg/kg per day (10 mL/kg volume), twice daily (morning and evening) from postnatal day 30 to postnatal day 86; the vehicle group received 0.5% methylcellulose alone; 3. Motor function was assessed weekly using the rotarod test: mice were trained to stay on a rotating rod (starting speed = 5 rpm, accelerating at 0.1 rpm/s), and the latency to fall (maximum 300 seconds) was recorded; 4. At the end of treatment (postnatal day 86), mice were euthanized, and brains were harvested, fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned (5 μm thick); hippocampal sections were stained with TUNEL reagent to count apoptotic neurons [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Mean oral bioavailability is 97%. Metabolism / Metabolites There is no evidence that miglustat is metabolized in humans. Biological Half-Life The effective half-life of miglustat is approximately 6 to 7 hours. |
| Toxicity/Toxicokinetics |
In the CFTR F508del/F508del mouse study:
- No mortality, weight loss, or obvious signs of toxicity (e.g., abnormal behavior, reduced activity) were observed in mice treated with miglustat (200 mg/kg per day for 6 days) compared to vehicle-treated mice [1]
In the NPC1⁻/⁻ mouse study: - miglustat treatment (50 mg/kg per day for 8 weeks) did not cause significant changes in liver function markers (alanine transaminase, ALT; aspartate transaminase, AST) or renal function markers (blood urea nitrogen, BUN; creatinine) compared to vehicle-treated NPC1⁻/⁻ mice (measured via clinical chemistry analysis of serum samples) [2] No data on plasma protein binding, drug-drug interactions, or median lethal dose (LD₅₀) were reported in the specified literatures [1][2] |
| References | |
| Additional Infomation |
Miglustat exerts its biological effects primarily by inhibiting glucosylceramide synthase, which reduces the biosynthesis of glycosphingolipids—lipids that are abnormally accumulated in diseases like cystic fibrosis and Niemann-Pick type C (NPC) disease [1][2]
In cystic fibrosis, the anti-inflammatory activity of miglustat (reducing IL-8 secretion) may help alleviate airway inflammation, a key pathological feature of the disease, while its ability to restore F508del-CFTR function addresses the underlying defect in ion transport [1] In NPC disease, miglustat’s restoration of synaptic plasticity (LTP) and reduction of neuronal apoptosis suggest it may have neuroprotective effects, which could help slow the progression of neurological symptoms in NPC disease [2] |
| Molecular Formula |
C10H21NO4
|
|---|---|
| Molecular Weight |
255.7390
|
| Exact Mass |
255.123
|
| Elemental Analysis |
C, 46.96; H, 8.67; Cl, 13.86; N, 5.48; O, 25.02
|
| CAS # |
210110-90-0
|
| Related CAS # |
Miglustat;72599-27-0;Miglustat-d9 hydrochloride;1883545-57-0
|
| PubChem CID |
6603107
|
| Appearance |
White to light brown solid powder
|
| Boiling Point |
421.2ºC at 760 mmHg
|
| Melting Point |
169-172ºC
|
| Flash Point |
208.5ºC
|
| Vapour Pressure |
7.37E-09mmHg at 25°C
|
| Hydrogen Bond Donor Count |
5
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
16
|
| Complexity |
190
|
| Defined Atom Stereocenter Count |
4
|
| SMILES |
CCCCN1C[C@@H]([C@H]([C@@H]([C@H]1CO)O)O)O.Cl
|
| InChi Key |
QPAFAUYWVZMWPR-ZSOUGHPYSA-N
|
| InChi Code |
InChI=1S/C10H21NO4.ClH/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H31H/t7-,8+,9-,10-/m1./s1
|
| Chemical Name |
(2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride
|
| Synonyms |
OGT918; OGT 918; OGT-918; N-butyldeoxynojirimycin; (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;hydrochloride; 874-729-5; RefChem:397514; 210110-90-0; Miglustat hydrochloride; Miglustat (hydrochloride); N-Butyldeoxynojirimycin hydrochloride; N-Butyldeoxynojirimycin.HCl; NB-DNJ; Miglustat hydrochloride; Zavesca.
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~65 mg/mL (~254.16 mM)
H2O : ≥ 34 mg/mL (~132.95 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (12.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3.25 mg/mL (12.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3.25 mg/mL (12.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (391.02 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.9102 mL | 19.5511 mL | 39.1022 mL | |
| 5 mM | 0.7820 mL | 3.9102 mL | 7.8204 mL | |
| 10 mM | 0.3910 mL | 1.9551 mL | 3.9102 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
A Study Comparing ATB200/AT2221 With Alglucosidase Alfa/Placebo in Adult Subjects With Late-onset Pompe Disease
CTID: NCT03729362
Phase: Phase 3 Status: Completed
Date: 2023-09-11
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
