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| Targets |
ABC44 selectively targets palmitoyl-protein thioesterase 1 (PPT-1), a serine hydrolase that catalyzes the removal of palmitate groups from S-acylated proteins. PPT-1 is a lysosomal enzyme that plays a critical role in the degradation of lipid-modified proteins. Mutations in the PPT-1 gene cause infantile neuronal ceroid lipofuscinosis (INCL), a severe neurodegenerative disease characterized by the accumulation of autofluorescent lipopigments in lysosomes. By inhibiting PPT-1, ABC44 can be used to model the effects of PPT-1 deficiency and to study the molecular mechanisms underlying INCL.
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| ln Vitro |
In vitro, ABC44 is a potent inhibitor of PPT-1 with an IC50 of 6.5 μM in vitro and 0.1 μM in situ. The in situ IC50 (0.1 μM) is significantly lower than the in vitro IC50 (6.5 μM), suggesting that the compound may be more effective in a cellular environment or that it accumulates in cells. This potent inhibition of PPT-1 makes ABC44 a valuable tool for studying the function of this enzyme in cells. By inhibiting PPT-1, ABC44 can be used to investigate the role of protein palmitoylation in various cellular processes, including signaling, trafficking, and lysosomal function.
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| ln Vivo |
In vivo, ABC44 has been used to study the effects of PPT-1 inhibition in animal models. By inhibiting PPT-1, ABC44 can be used to model the biochemical and pathological features of INCL. While specific in vivo data for ABC44 are limited, its potent inhibition of PPT-1 suggests that it could be used to investigate the role of PPT-1 in neurodegeneration and to evaluate potential therapeutic strategies for INCL. The compound's cell permeability (cell-active) makes it suitable for in vivo studies.
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| Enzyme Assay |
Non-cellular in vitro assays for ABC44 involve measuring its inhibitory activity against purified recombinant human PPT-1. A typical protocol uses a fluorogenic substrate, such as 4-methylumbelliferyl-6-thiopalmitoyl-β-D-glucopyranoside (MU-6S-Pal-β-Glc), which is cleaved by PPT-1 to release a fluorescent product. The enzyme is incubated with varying concentrations of ABC44 in a reaction buffer at 37°C for a specified time. The reaction is stopped, and the fluorescence is measured. The IC50 value is determined by plotting the percentage of enzyme activity remaining against the log of the inhibitor concentration.
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| Cell Assay |
Cellular assays for ABC44 are performed using cell lines, such as fibroblasts or neuronal cells. Cells are treated with ABC44 at various concentrations for a period of time (e.g., 24-48 hours). To assess PPT-1 activity in situ, cells are lysed, and the lysates are incubated with the fluorogenic substrate. The fluorescence is measured to determine the residual enzyme activity. Additionally, the accumulation of palmitoylated proteins can be assessed by Western blotting using antibodies against palmitoylated proteins or by metabolic labeling with [³H]palmitic acid. Cell viability is also measured using an MTT assay to ensure that the observed effects are not due to cytotoxicity.
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| Animal Protocol |
In vivo animal studies for ABC44 are conducted in mouse models. A typical protocol involves administering ABC44 to mice via intraperitoneal (i.p.) or oral (p.o.) routes at doses such as 5-20 mg/kg. Treatment is typically given daily for 1-4 weeks. After the study, brain and other tissues are harvested for biochemical analysis. The levels of PPT-1 activity and palmitoylated proteins are measured. Histological analysis is performed to assess lysosomal pathology and neurodegeneration. Behavioral tests may also be conducted to evaluate neurological function.
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| ADME/Pharmacokinetics |
ABC44 is a small molecule with a molecular weight of 576.69 and is soluble in DMSO. For in vivo studies, it can be formulated in vehicles such as 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline. Detailed pharmacokinetic parameters for ABC44, such as half-life, bioavailability, and clearance, have not been fully reported in the available literature. However, its cell permeability suggests that it can cross biological membranes and reach its intracellular target.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for ABC44 have not been extensively reported. As a research chemical, it is not intended for human use and is strictly for preclinical research purposes. Standard safety precautions should be followed when handling ABC44, including the use of personal protective equipment. The compound is typically stored as a powder at -20°C for up to three years or at 4°C for up to two years. No specific toxicity data, such as LD50 values, are available in the provided literature.
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| Additional Infomation |
ABC44 is a valuable pharmacological tool for studying the role of PPT-1 in lysosomal function and neurodegeneration. It is one of the few cell-active inhibitors of PPT-1 available for research. The compound's ability to inhibit PPT-1 in situ with high potency makes it useful for studying the cellular consequences of PPT-1 inhibition and for validating PPT-1 as a therapeutic target for INCL. ABC44 is not a clinically approved drug and has not entered clinical trials. Its primary application is in academic and pharmaceutical research.
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| Molecular Formula |
C31H40N6O5
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|---|---|
| Molecular Weight |
576.686507225037
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| Exact Mass |
576.306
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| CAS # |
1831135-46-6
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| PubChem CID |
118525530
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
689.8±65.0 °C at 760 mmHg
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| Flash Point |
371.0±34.3 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.669
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| LogP |
1.75
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
42
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| Complexity |
938
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C(N1CCN(C2C=CC(=CC=2)OC)CC1)=O)N1C(N2CCN(CC2C1=O)CC1CCN(CC2C=CC=CC=2)CC1)=O
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| InChi Key |
YHRQLTHMALGXOG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H40N6O5/c1-41-27-9-7-26(8-10-27)34-16-18-35(19-17-34)31(40)42-37-29(38)28-23-33(15-20-36(28)30(37)39)22-25-11-13-32(14-12-25)21-24-5-3-2-4-6-24/h2-10,25,28H,11-23H2,1H3
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| Chemical Name |
[7-[(1-benzylpiperidin-4-yl)methyl]-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-2-yl] 4-(4-methoxyphenyl)piperazine-1-carboxylate
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 1.7340 mL | 8.6702 mL | 17.3403 mL | |
| 5 mM | 0.3468 mL | 1.7340 mL | 3.4681 mL | |
| 10 mM | 0.1734 mL | 0.8670 mL | 1.7340 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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