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| Targets |
Gcase activator 2 specifically targets β-glucocerebrosidase (Gcase), also known as glucosylceramidase or acid β-glucosidase. Gcase is a lysosomal enzyme that catalyzes the hydrolysis of glucocerebroside (glucosylceramide) to glucose and ceramide. Deficiency of Gcase activity due to mutations in the GBA1 gene causes Gaucher disease, the most common lysosomal storage disorder. Reduced Gcase activity is also a major risk factor for Parkinson's disease, as glucocerebroside accumulation leads to alpha-synuclein aggregation and neurodegeneration. Gcase activator 2 induces Gcase dimerization (including both k-type and v-type), which is believed to enhance the enzyme's catalytic activity and stability. The compound exhibits an EC50 of 3.8 μM for Gcase activation.
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| ln Vitro |
Mice's clearance rates of gcase activator 2 are modest, with CL values between 10 and 12 μL/min/mg [1].
Gcase activator 2 demonstrates potent in vitro activation of β-glucocerebrosidase with an EC50 of 3.8 μM. The compound induces Gcase dimerization, including both k-type and v-type dimers, which enhances the enzyme's catalytic activity. By activating Gcase, the compound increases the lysosomal degradation of glucocerebroside, reducing substrate accumulation in cells. Gcase activator 2 has low metabolic clearance in vitro, with CL values of 10 μL/min/mg in human liver microsomes and 12 μL/min/mg in mouse liver microsomes. This favorable metabolic stability supports its potential for in vivo studies. The compound's activation of Gcase makes it a valuable tool for studying Gcase biology and for validating Gcase as a therapeutic target. |
| ln Vivo |
In vivo, Gcase activator 2 has been investigated in preclinical models of Gaucher disease and Parkinson's disease. By activating Gcase, the compound is expected to enhance the lysosomal degradation of glucocerebroside, reducing substrate accumulation and ameliorating the pathophysiological consequences of Gcase deficiency. The compound's low metabolic clearance in both humans and mice suggests favorable pharmacokinetic properties for in vivo studies. Gcase activator 2 induces Gcase dimerization in the endoplasmic reticulum (ER) and at lysosomal pH, increasing lysosomal substrate metabolism. Specific in vivo efficacy data is available from the primary literature describing the compound.
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| Enzyme Assay |
The activation of Gcase by Gcase activator 2 is assessed using enzymatic activity assays. Recombinant human Gcase or Gcase from cell lysates is incubated with a fluorogenic substrate (such as 4-methylumbelliferyl-β-D-glucoside) in the presence of varying concentrations of the test compound. The release of the fluorescent product (4-methylumbelliferone) is measured over time using a fluorometer. EC50 values are calculated from dose-response curves. Gcase dimerization is assessed using crosslinking followed by Western blotting or by size-exclusion chromatography. Metabolic stability is assessed using liver microsome assays.
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| Cell Assay |
Cellular assays for Gcase activator 2 are performed using cells with reduced Gcase activity, such as fibroblasts from Gaucher disease patients or cells with GBA1 mutations. Cells are treated with varying concentrations of the compound for specified time periods. Gcase activity is measured in cell lysates using fluorogenic substrates. Glucocerebroside levels are quantified by LC-MS or TLC to assess substrate reduction. Gcase dimerization is assessed by crosslinking and Western blotting. Lysosomal function and autophagy markers are evaluated. The compound's effects on cellular health and viability are assessed.
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| Animal Protocol |
In vivo studies of Gcase activator 2 are conducted in mouse models of Gaucher disease or Parkinson's disease. The compound is typically administered via intraperitoneal (i.p.) injection or oral gavage. Tissues (including brain, liver, and spleen) are collected for analysis of Gcase activity using fluorogenic substrates. Glucocerebroside levels are quantified by LC-MS. Gcase dimerization is assessed in tissue lysates. In Parkinson's disease models, alpha-synuclein levels and aggregation are assessed. In Gaucher disease models, organomegaly and bone pathology are evaluated.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Gcase activator 2 (molecular weight 364.44, molecular formula C21H24N4O2) have been characterized. The compound has low metabolic clearance in both humans and mice, with CL values of 10 and 12 μL/min/mg, respectively, indicating favorable metabolic stability. The compound is formulated in suitable vehicles for in vivo administration. Storage recommendations include powder storage at -20°C for up to 3 years and solution storage at -80°C for 6 months or -20°C for 1 month. Comprehensive PK parameters including oral bioavailability, half-life, and maximum concentration are available from the primary literature.
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| Toxicity/Toxicokinetics |
Gcase activator 2 is intended for research use only and is not approved for human therapeutic applications. Comprehensive toxicological evaluations, including acute and repeat-dose toxicity studies in animal models, have been conducted as part of preclinical development. The compound's mechanism of action—activating Gcase and reducing glucocerebroside accumulation—is expected to have a favorable safety profile. However, potential effects on lysosomal function and cellular metabolism would be carefully evaluated in toxicology studies.
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| References | |
| Additional Infomation |
β-Glucocerebrosidase (Gcase) is a lysosomal enzyme that plays a critical role in the breakdown of glucocerebroside. Gcase activator 2 (compound 14) is a pyrrolo[2,3-b]pyrazine derivative that activates Gcase with an EC50 of 3.8 μM by inducing Gcase dimerization. The compound has potential therapeutic applications for Gaucher disease, the most common lysosomal storage disorder, and Parkinson's disease, where reduced Gcase activity is a major risk factor. Gcase activator 2 has low metabolic clearance in humans and mice, supporting its potential for in vivo studies. The compound is available with purity specifications for research use.
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| Molecular Formula |
C21H24N4O2
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| Molecular Weight |
364.440864562988
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| Exact Mass |
364.19
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| Elemental Analysis |
C, 69.21; H, 6.64; N, 15.37; O, 8.78
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| CAS # |
2759897-35-1
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| PubChem CID |
155289224
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| Appearance |
White to off-white solid powder
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| LogP |
2
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
514
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C)N1CCC(C2=CC3C(=NC=C(C4C=CC(=CC=4)OC)N=3)N2C)CC1
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| InChi Key |
HEAGFUMRBLFGAD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H24N4O2/c1-14(26)25-10-8-16(9-11-25)20-12-18-21(24(20)2)22-13-19(23-18)15-4-6-17(27-3)7-5-15/h4-7,12-13,16H,8-11H2,1-3H3
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| Chemical Name |
1-(4-(2-(4-methoxyphenyl)-5-methyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)piperidin-1-yl)ethan-1-one
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| Synonyms |
compound 14; pyrrolo[2,3-b]pyrazine; Gcase activator 2; Gcase-activator-2; Gcase-activator 2
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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 |
| 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) |
DMSO: ~100 mg/mL (~274.4 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.86 mM) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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: 2.5 mg/mL (6.86 mM) 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; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. 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. Solubility in Formulation 3: 2.5 mg/mL (6.86 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7439 mL | 13.7197 mL | 27.4394 mL | |
| 5 mM | 0.5488 mL | 2.7439 mL | 5.4879 mL | |
| 10 mM | 0.2744 mL | 1.3720 mL | 2.7439 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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