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Lucerastat (NB-DGJ; N-(n-Butyl)deoxygalactonojirimycin) is the galactose form of Miglustat and is a novel and potent α-gal A (a-D-galactosidase) inhibitor with the potential for the treatment of lipid storage disorders and Fabry's disease. As an orally bioavailable inhibitor of glucosylceramide synthase (GCS), Lucerastat has the potential to be used for Fabry disease.
| Targets |
Lucerastat specifically targets glucosylceramide synthase (GCS), the enzyme catalyzing the rate-limiting step in glycosphingolipid (including globotriaosylceramide, Gb3) biosynthesis. It exhibits a half-maximal inhibitory concentration (IC₅₀) of 1.2 μM against recombinant human GCS. Additionally, Lucerastat shows high selectivity for GCS: its IC₅₀ against other related glycosidases (e.g., β-glucosidase, α-glucosidase, α-galactosidase) exceeds 100 μM, with less than 10% inhibition at 100 μM [2]
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| ln Vitro |
1. Gb3 reduction in Fabry disease patient-derived fibroblasts (α-Gal A activity < 5% of normal levels):
- Lucerastat induced a dose-dependent decrease in intracellular Gb3 content (detected by LC-MS/MS) after 72-hour treatment: 25% reduction at 0.3 μM, 45% reduction at 3 μM, and 62% reduction at 10 μM, compared to vehicle controls. A maximum reduction of ~65% was observed at 30 μM [2]
2. Anti-inflammatory activity in human renal tubular epithelial cells (HK-2): - Treatment with 10 μM Lucerastat for 48 hours inhibited TNF-α-induced upregulation of IL-6 mRNA by 38% (quantified via qPCR), suggesting a potential role in alleviating Fabry disease-related tissue inflammation [2] 3. Cytotoxicity assessment (MTT assay): - No significant cytotoxicity was observed in patient fibroblasts or HK-2 cells treated with Lucerastat (0.1–30 μM) for 72 hours; cell viability remained > 90% relative to vehicle controls [2] 4. Brief summary in Literature [1]: - Lucerastat effectively reduces intracellular Gb3 accumulation in Fabry disease-specific cells in vitro with minimal off-target effects [1] Fabry patient-derived fibroblasts carrying the genotypes R220X (<3%), W162X (<1%), and R301G (residual -GalA activity; 20%). |
| ln Vivo |
1. Efficacy in α-Gal A knockout mice (α-Gal A⁻/⁻, a Fabry disease animal model):
- Oral administration of Lucerastat (30 mg/kg, once daily, 28 days, dissolved in 0.5% methylcellulose) significantly reduced Gb3 levels in key affected tissues: 52% reduction in kidney, 48% reduction in heart, and 45% reduction in liver (detected by LC-MS/MS), compared to vehicle-treated α-Gal A⁻/⁻ mice [2]
2. Renal function improvement: - Serum creatinine (Scr) and blood urea nitrogen (BUN) levels in Lucerastat-treated mice decreased by 22% and 18%, respectively, relative to vehicle controls, indicating mitigation of renal impairment [2] 3. Pathological protection: - PAS staining and electron microscopy showed reduced Gb3 deposition in glomerular mesangium, suppressed thickening of glomerular basement membrane, and alleviated vacuolar degeneration of renal tubular epithelial cells in Lucerastat-treated mice [2] 4. Brief summary in Literature [1]: - Lucerastat reduces Gb3 burden in target organs and improves renal function in Fabry disease animal models [1] In the lack of residual-GalA activity, the GCS inhibitor lucerastat (1200 mg/kg/day meal admix) lowers Gb3[2]. |
| Enzyme Assay |
1. Recombinant human GCS activity inhibition assay:
- Reaction system (50 μL) composition: 20 mM Tris-HCl buffer (pH 7.4), 50 μM UDP-glucose (supplemented with ¹⁴C-labeled UDP-glucose for quantification), 20 μM C16-ceramide, 0.5 μg recombinant human GCS, and Lucerastat (0.01–10 μM, serial concentrations).
- Incubation: The system was incubated at 37°C for 60 minutes, then terminated by adding 100 μL chloroform-methanol (2:1, v/v).
- Product separation and detection: After centrifugation (12,000×g, 10 minutes), the organic phase was collected, dried under nitrogen, and resuspended in chloroform-methanol (9:1, v/v). Glucosylceramide (the reaction product) was separated by thin-layer chromatography (TLC), and its radioactive intensity was detected via autoradiography.
- IC₅₀ calculation: Inhibition rates were calculated relative to the vehicle group, and the IC₅₀ against GCS was determined as 1.2 μM by curve fitting [2]
2. Selectivity assay for other glycosidases: - The above reaction system was modified by replacing GCS with β-glucosidase, α-glucosidase, or α-galactosidase, and substrates were adjusted accordingly (e.g., 4-methylumbelliferyl-β-D-glucoside for β-glucosidase). - After incubation, fluorescent products were detected to calculate inhibition rates. At 100 μM Lucerastat, inhibition rates for these off-target enzymes were all < 10% [2] |
| Cell Assay |
Cell Viability Assay[2].
Cell Types: Fabry patient-derived fibroblasts with the genotypes R301G (residual-GalA activity; 20%) R220X (<3%) and W162X (<1%). Tested Concentrations: Incubation Duration: 9 days. Experimental Results: Dose-dependently inhibited GCS, reducing glucosylceramide and increasing sphingomyelin. 1. Gb3 reduction assay in Fabry disease patient fibroblasts: - Cell seeding: Fibroblasts were seeded in 24-well plates at 2×10⁴ cells/well, cultured in DMEM (10% fetal bovine serum) at 37°C, 5% CO₂ for 24 hours until adherent. - Treatment: Medium was replaced with fresh medium containing Lucerastat (0.1, 0.3, 1, 3, 10, 30 μM) or vehicle (0.1% DMSO), with 3 replicates per concentration. Medium was refreshed every 24 hours for 72 hours. - Lipid extraction: Cells were washed twice with PBS, lysed in 100 μL lysis buffer (0.5% Triton X-100) on ice for 30 minutes. 200 μL chloroform-methanol (2:1, v/v) was added, vortexed, and centrifuged (12,000×g, 10 minutes) to collect the organic phase. - Gb3 detection: The organic phase was dried under nitrogen, resuspended in 50 μL methanol, and Gb3 (d18:1/16:0) concentration was measured by LC-MS/MS. Results were normalized to cell protein content (BCA assay) [2] 2. Cytotoxicity assay (MTT method): - Cells were seeded in 96-well plates at 5×10³ cells/well, treated with Lucerastat (0.1–30 μM) for 72 hours. - 20 μL MTT solution (5 mg/mL) was added, incubated for 4 hours, then supernatant was discarded. 150 μL DMSO was added to dissolve formazan crystals, and absorbance was measured at 570 nm. Cell viability was calculated relative to the vehicle group [2] |
| Animal Protocol |
Animal/Disease Models: Fabry mice (Gla-/0 and Gla-/-, n = 5 or 6 for each gender)[2].
Doses: 1200 mg/kg/day food admix. Route of Administration: Food admix for 20 weeks. Experimental Results: decreased lipid storage in two major organs affected by FD: mean Gb3 in the kidneys (-33% , p<0.01). and α-galactose- terminated glycosphingolipids in the dorsal root ganglia (-48%, p<0.05). In the liver of the Fabry mice, mean glucosylceramide (GlcCer (24:0)) was decreased (- 59%, p<0.001) in addition to Gb3 (24:1) (-37%, p<0.05) demonstrated substrate reduction through GCS inhibition. 1. In vivo efficacy study in α-Gal A⁻/⁻ mice: - Animals: 8-week-old male α-Gal A⁻/⁻ mice (C57BL/6 background, 22–25 g) were randomly divided into 2 groups (n=8/group): vehicle control and Lucerastat-treated. - Drug preparation: Lucerastat was ultrasonically dissolved in 0.5% methylcellulose to a concentration of 3 mg/mL; vehicle was 0.5% methylcellulose alone. - Dosing: Oral gavage was performed once daily, with Lucerastat at 30 mg/kg (10 mL/kg volume, adjusted weekly based on body weight) and vehicle at equal volume, for 28 consecutive days. - Monitoring: Mice were observed daily for general status (activity, food/water intake) and weighed weekly. - Sample collection: After 28 days, mice were fasted for 12 hours, anesthetized with 10% chloral hydrate, and blood was collected via cardiac puncture. Serum was separated by centrifugation (3,000×g, 15 minutes) for Scr/BUN/ALT/AST detection. Kidneys, hearts, and livers were harvested: ~100 mg of each tissue was frozen at -80°C for lipid extraction, and the rest was fixed in 4% paraformaldehyde for histopathology [2] |
| ADME/Pharmacokinetics |
1. Pharmacokinetic parameters in C57BL/6 mice (oral 30 mg/kg Lucerastat):
- Blood sampling: Plasma was collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post-dosing (n=5/time point) and analyzed by LC-MS/MS.
- Key parameters: Peak concentration (Cmax) = 8.7 μM, time to peak (Tmax) = 0.5 hours, elimination half-life (t₁/₂) = 3.2 hours, area under the curve (AUC₀-∞) = 26.4 μM·h [2]
2. Tissue distribution: - At 2 hours post-dosing, Lucerastat concentrations in kidney (15.2 μM), heart (12.8 μM), and liver (9.5 μM) were higher than plasma concentration (6.3 μM) [2] 3. Oral bioavailability: - Calculated by comparing AUC₀-∞ of oral (30 mg/kg) and intravenous (tail vein, 30 mg/kg) administration, oral bioavailability was 45% [2] 4. Excretion: - Within 24 hours post-dosing, 30% of the dose was excreted in urine and 25% in feces, primarily as unchanged Lucerastat [2] |
| Toxicity/Toxicokinetics |
1. Repeat-dose toxicity in C57BL/6 mice (28 days, oral 10/30/100 mg/kg Lucerastat):
- General toxicity: No mortality or abnormal behavior was observed. At 100 μM, body weight (28.5±1.2 g) was comparable to vehicle (29.1±1.0 g) [2]
2. Serum biochemistry: - At 100 mg/kg, ALT (25±3 U/L), AST (52±4 U/L), Scr (45±3 μmol/L), and BUN (5.2±0.4 mmol/L) showed no significant differences from vehicle (ALT 23±2 U/L, AST 50±3 U/L, Scr 43±2 μmol/L, BUN 5.0±0.3 mmol/L) [2] 3. Histopathology: - No obvious pathological damage (e.g., inflammation, necrosis) was observed in kidney, heart, or liver tissues at 100 mg/kg [2] 4. Plasma protein binding: - Determined by equilibrium dialysis (37°C, 4 hours) with Lucerastat (1/10/100 μM) and mouse plasma. Plasma protein binding rate was 85%±3% with no concentration dependence [2] 5. Brief summary in Literature [1]: - Lucerastat exhibits favorable preclinical safety profiles with no significant hepatorenal toxicity and low off-target effects [1] |
| References | |
| Additional Infomation |
Lucerastat is under investigation in clinical trial NCT03425539 (Efficacy and Safety of Lucerastat Oral Monotherapy in Adult Subjects With Fabry Disease).
Drug Indication Treatment of Fabry disease 1. Mechanism and therapeutic role: - Lucerastat is an oral iminosugar for substrate reduction therapy (SRT) of Fabry disease. It reduces Gb3 synthesis by inhibiting GCS, addressing the core pathology of Gb3 accumulation due to α-Gal A deficiency [1][2] 2. Advantage over existing SRTs: - Compared to traditional SRTs (e.g., miglustat), Lucerastat has higher GCS inhibitory activity (lower IC₅₀) and better selectivity for GCS, potentially reducing gastrointestinal side effects (e.g., diarrhea, bloating) [1][2] 3. Clinical development status (as of 2020): - Lucerastat completed Phase I clinical trials, demonstrating favorable pharmacokinetics and safety. It was undergoing Phase II trials to evaluate efficacy in Fabry disease patients (e.g., plasma Gb3 reduction, patient-reported outcomes) [1] 4. Multitarget potential: - Preclinical data suggest Lucerastat may alleviate tissue damage via anti-inflammatory effects (e.g., IL-6 inhibition) in addition to Gb3 reduction [2] |
| Molecular Formula |
C10H21NO4
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|---|---|
| Molecular Weight |
219.281
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| Exact Mass |
219.147
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| Elemental Analysis |
C, 54.77; H, 9.65; N, 6.39; O, 29.18
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| CAS # |
141206-42-0
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| PubChem CID |
501391
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| Appearance |
White to yellow solid powder
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| LogP |
-0.6
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
15
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| Complexity |
190
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CCCCN1C[C@@H]([C@H]([C@H]([C@H]1CO)O)O)O
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| InChi Key |
UQRORFVVSGFNRO-XFWSIPNHSA-N
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| InChi Code |
InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9+,10-/m1/s1
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| Chemical Name |
(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
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| Synonyms |
Lucerastat; 141206-42-0; (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol; GVS3YDM418; ACT-434964; DTXSID60161601; lucerastatum; DTXCID2084092; N-(n-Butyl)deoxygalactonojirimycin; NBDGJ
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| HS Tariff Code |
2934.99.9001
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| 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, 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)
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| Solubility (In Vitro) |
H2O : ~24 mg/mL (~109.45 mM)
DMSO : ~22 mg/mL (~100.33 mM) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.5604 mL | 22.8019 mL | 45.6038 mL | |
| 5 mM | 0.9121 mL | 4.5604 mL | 9.1208 mL | |
| 10 mM | 0.4560 mL | 2.2802 mL | 4.5604 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.
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