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| Targets |
beta-Secretase Inhibitor IV primarily targets beta-site amyloid protein cleaving enzyme 1 (BACE-1), also known as beta-secretase 1. BACE-1 is a transmembrane aspartyl protease that cleaves the amyloid precursor protein (APP) at the beta-secretase site, initiating the production of amyloid-beta peptides that aggregate to form amyloid plaques in Alzheimer's disease. The compound also inhibits BACE-2 (beta-secretase 2) with an IC₅0 of 230 nM. beta-Secretase Inhibitor IV binds to the active site of BACE-1 and potently blocks its proteolytic activity. The compound's hydroxyethylamine motif is a key pharmacophore that interacts with the catalytic aspartate residues in the BACE-1 active site. Additionally, the compound may inhibit cathepsin D.
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| ln Vitro |
β-secretase inhibitor IV (compound 2) has an EC50 of 43 nM in cell culture experiments, inhibiting the synthesis of Aβ peptide. With an IC50 at 30 nM, β-Secretase Inhibitor IV efficiently suppresses sAPP_NF and EV40 secretion in HEK293T cells[1].
beta-Secretase Inhibitor IV demonstrates potent in vitro inhibitory activity against BACE-1 with an IC₅0 of 15 nM for the human enzyme. The compound also inhibits BACE-2 with an IC₅0 of 230 nM, showing selectivity for BACE-1 over BACE-2. As a cell-permeable inhibitor, beta-Secretase Inhibitor IV can effectively enter cells and inhibit intracellular BACE-1 activity. In cell-based assays, the compound has been shown to block the proteolytic activity of BACE-1 and reduce the production of amyloid-beta peptides, as demonstrated by its ability to inhibit sAPP_NF in HEK293-APPNF cells with an IC₅0 of 29 nM. The compound's high potency and cell permeability make it a valuable tool for studying the role of BACE-1 in Alzheimer's disease pathology. |
| ln Vivo |
In vivo activity data for beta-Secretase Inhibitor IV are limited, as the compound is primarily used as a research tool for studying BACE-1 inhibition in vitro and in cell-based systems. Based on its potent inhibition of BACE-1 (IC₅0 = 15 nM) and cell permeability, the compound has the potential to reduce amyloid-beta production in vivo. However, comprehensive pharmacokinetic and pharmacodynamic studies in animal models have not been extensively reported in the available literature. The compound's isophthalamide structure with a hydroxyethylamine motif suggests that it may have suitable properties for central nervous system penetration, but detailed in vivo studies are needed to confirm its efficacy and safety in animal models of Alzheimer's disease.
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| Enzyme Assay |
The in vitro enzyme/receptor binding assay for beta-Secretase Inhibitor IV typically involves measuring its inhibitory activity against BACE-1 using fluorogenic or FRET-based protease activity assays. The assay system includes recombinant human BACE-1 enzyme, a suitable peptide substrate (such as a fluorogenic APP-derived peptide that contains the beta-secretase cleavage site), and assay buffer (typically containing sodium acetate, Triton X-100, and DMSO). beta-Secretase Inhibitor IV is added at varying concentrations (0.1 nM to 100 uM) and pre-incubated with the enzyme before substrate addition. The reaction is incubated at 37degC for 30-60 minutes, and the cleavage of the substrate is monitored by measuring fluorescence (excitation/emission typically around 320/420 nm for FRET substrates). IC₅0 values are calculated from dose-response curves using nonlinear regression analysis.
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| Cell Assay |
The in vitro cell-based assay for beta-Secretase Inhibitor IV involves culturing cells that express BACE-1 and APP, such as HEK293 cells stably expressing APP or neuronal cell lines. Cells are typically seeded in multi-well plates and treated with varying concentrations of the compound (0.1 nM to 10 uM) for 4-24 hours in appropriate culture media at 37degC with 5% CO2. Following treatment, the levels of secreted amyloid-beta peptides (Abeta40 and Abeta42) in the conditioned media are measured using ELISA or MSD assays. Additionally, the levels of sAPPbeta (the BACE-1 cleavage product of APP) can be assessed by Western blot analysis using specific antibodies. Cell viability is assessed using standard assays such as MTT or LDH release to ensure that observed effects are not due to cytotoxicity. The compound is cell-permeable.
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| Animal Protocol |
In vivo animal studies for beta-Secretase Inhibitor IV have not been extensively documented in the literature. Based on the compound's mechanism as a BACE-1 inhibitor, potential animal studies would typically involve administration of the compound via intraperitoneal, intravenous, or oral routes in transgenic mouse models of Alzheimer's disease (such as APP/PS1 or 5xFAD mice). Dosing would be determined based on preliminary pharmacokinetic data and solubility profiles. Common endpoints in such studies would include evaluation of amyloid-beta levels in brain and cerebrospinal fluid, assessment of amyloid plaque burden by immunohistochemistry, and monitoring of behavioral and cognitive outcomes. However, comprehensive in vivo efficacy and toxicity studies have not been widely reported for this compound.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of beta-Secretase Inhibitor IV have not been fully characterized in the literature. The compound has a molecular weight of 578.72 g/mol and a molecular formula of C31H3₈N4O₅S. It is a solid with a purity of ≥95%. As a cell-permeable inhibitor, the compound can cross cell membranes, suggesting it may have suitable properties for penetration of the blood-brain barrier. The compound's isophthalamide structure with a hydroxyethylamine motif is characteristic of BACE-1 inhibitors designed for central nervous system activity. However, detailed pharmacokinetic parameters such as half-life, bioavailability, brain penetration, and clearance have not been extensively reported in the available literature. The compound is intended for research purposes only.
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| Toxicity/Toxicokinetics |
Toxicity data for beta-Secretase Inhibitor IV are limited, as the compound is a research-use inhibitor and has not undergone extensive toxicological characterization. Standard safety precautions should be followed when handling this compound, including the use of appropriate personal protective equipment such as gloves and lab coats to prevent skin contact and inhalation of dust. The compound should be handled in a well-ventilated area. In case of accidental exposure, rinse affected areas with plenty of water and seek medical attention if irritation persists. Proper waste disposal procedures should be observed in accordance with local regulations. As with all research chemicals, exposure should be minimized and the compound should be stored securely away from incompatible materials.
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| References | |
| Additional Infomation |
Reports indicate that N-[(1S,2R)-1-benzyl-3-(cyclopropylamino)-2-hydroxypropyl]-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]isophthalamide has been found in Asian boletus, and relevant data are available for reference.
beta-Secretase Inhibitor IV (CAS#: 797035-11-1) is a research-grade BACE-1 inhibitor with the molecular formula C31H3₈N4O₅S and a molecular weight of 578.72. This cell-permeable isophthalamide compound contains a hydroxyethylamine motif that binds to the active site of BACE-1 and potently blocks its proteolytic activity. The compound exhibits an IC₅0 of 15 nM for human BACE-1 and 230 nM for human BACE-2. In cell-based assays, it inhibits sAPP_NF in HEK293-APPNF cells with an IC₅0 of 29 nM. beta-Secretase Inhibitor IV is used in research focused on Alzheimer's disease and the amyloid cascade hypothesis. The compound has a purity of ≥95% and is intended for research purposes only. No clinical trials or regulatory approvals have been reported. |
| Molecular Formula |
C31H38N4O5S
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| Molecular Weight |
578.72222
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| Exact Mass |
578.256
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| CAS # |
797035-11-1
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| Related CAS # |
797035-11-1;
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| PubChem CID |
5287532
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
41
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| Complexity |
956
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O=S(N(C)C1=CC(C(N[C@@H](CC2=CC=CC=C2)[C@H](O)CNC3CC3)=O)=CC(C(N[C@H](C)C4=CC=CC=C4)=O)=C1)(C)=O
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| InChi Key |
VPNIQGRFZCTBEZ-SPTGULJVSA-N
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| InChi Code |
InChI=1S/C31H38N4O5S/c1-21(23-12-8-5-9-13-23)33-30(37)24-17-25(19-27(18-24)35(2)41(3,39)40)31(38)34-28(16-22-10-6-4-7-11-22)29(36)20-32-26-14-15-26/h4-13,17-19,21,26,28-29,32,36H,14-16,20H2,1-3H3,(H,33,37)(H,34,38)/t21-,28+,29-/m1/s1
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| Chemical Name |
3-N-[(2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl]-5-[methyl(methylsulfonyl)amino]-1-N-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide
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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 (~172.80 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.32 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: 2.5 mg/mL (4.32 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7280 mL | 8.6398 mL | 17.2795 mL | |
| 5 mM | 0.3456 mL | 1.7280 mL | 3.4559 mL | |
| 10 mM | 0.1728 mL | 0.8640 mL | 1.7280 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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