| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 100mg | |||
| Other Sizes |
| Targets |
AE-3763 specifically targets human neutrophil elastase (HNE), a serine protease enzyme. HNE is predominantly found in the azurophilic granules of neutrophils and plays a crucial role in the degradation of extracellular matrix proteins such as elastin and collagen. By binding to the active site of HNE, AE-3763 prevents the enzyme from interacting with its natural substrates. This inhibition is highly potent, with an IC50 value of 29 nM, indicating that a very low concentration is sufficient to halve the enzyme's activity. The compound's mechanism of action is to block the proteolytic activity of HNE, thereby mitigating the tissue damage and inflammation associated with its overactivity.
|
|---|---|
| ln Vitro |
AE-3763 possesses significant in vitro inhibitory activity against human neutrophil elastase and has extraordinarily high solubility and stability in water [1].
In vitro, AE-3763 demonstrates potent inhibitory activity against human neutrophil elastase. Its efficacy is quantified by an IC50 of 29 nM, which represents the concentration required to inhibit 50% of the enzyme's activity. In addition to its strong inhibitory effect, AE-3763 is characterized by extremely high solubility and stability in water. This high aqueous solubility is a significant advantage for biochemical assays and formulation, as it eliminates the need for organic solvents that could interfere with experimental results or cause cellular toxicity. |
| ln Vivo |
A substantial reduction in pulmonary edema and leukocyte infiltration was observed upon AE-3763 infusion. In a mouse model of lethal shock coupled with multiple organ failure, AE3763 markedly increased 24-hour survival. AE-3763, either given intravenously (ED50: 0.42 mg/kg/h) or as a bolus (1.2 mg/kg), reduced bleeding in a dose-dependent manner. Preliminary research results regarding the toxicity of AE-3763 to mice indicate that, even at a high dose of 300 mg/kg iv, there is no discernible adverse effect[1].
In vivo, AE-3763 has demonstrated significant efficacy in several animal models of disease. In a hamster model of elastase-induced lung hemorrhage, AE-3763 reduced bleeding in a dose-dependent manner. It also effectively inhibited edema and leukocyte infiltration into the lungs in models of LPS-induced lung injury. Furthermore, in a mouse model of fatal shock associated with multiple organ failure, treatment with AE-3763 significantly improved the 24-hour survival rate. These findings highlight the compound's potential to mitigate severe inflammatory and tissue-damaging responses in vivo. |
| Enzyme Assay |
Cell-free enzyme inhibition assays are the primary method for characterizing AE-3763's activity. A typical protocol involves pre-incubating the human neutrophil elastase enzyme with the test compound in an assay solution at 37degC for a short period, such as 4 minutes. Following this pre-incubation, a specific fluorogenic or chromogenic substrate for HNE is added. The enzymatic activity is then measured by monitoring the cleavage of the substrate, which produces a detectable signal. The IC50 value, which is 29 nM for AE-3763, is determined by plotting the percentage of enzyme activity remaining against the concentration of the inhibitor.
|
| Cell Assay |
In vitro cellular experiments with AE-3763 are designed to study its effects in a more complex biological environment. Typically, relevant cell types such as neutrophils or other inflammatory cells are cultured and stimulated to release elastase. These cells are then treated with varying concentrations of AE-3763. The compound's ability to inhibit the activity of the released elastase is measured, often by assessing the degradation of a specific substrate added to the cell culture medium. These experiments help to confirm the compound's potency in a cellular context and to evaluate its effects on cell-mediated processes like degranulation and the inflammatory response.
|
| Animal Protocol |
In vivo animal experiments with AE-3763 are conducted in various disease models to evaluate its therapeutic potential. For instance, in a hamster model, the compound is administered to evaluate its effect on elastase-induced lung hemorrhage. AE-3763 is given either as a bolus injection (e.g., 1.2 mg/kg) or by continuous intravenous infusion (e.g., with an ED50 of 0.42 mg/kg/h). Efficacy is assessed by measuring the reduction in hemorrhage. In a mouse model of LPS/galactosamine-induced acute multiple organ dysfunction, survival rates are monitored to determine the compound's protective effects. These studies demonstrate the compound's ability to reduce inflammation and improve survival in vivo.
|
| ADME/Pharmacokinetics |
AE-3763 has a molecular weight of 549.54 g/mol. Its exceptional aqueous solubility is a key pharmacokinetic property that facilitates its administration and distribution. In animal studies, it is typically administered via intravenous injection or infusion. Its high solubility likely contributes to favorable bioavailability and rapid distribution, which are important for its in vivo efficacy. The compound is stable as a powder and in solution under recommended storage conditions, and a LogP value of 1.4 indicates it has moderate lipophilicity.
|
| Toxicity/Toxicokinetics |
AE-3763 exhibits a favorable preclinical toxicity profile. In preliminary studies on mice, even high intravenous doses of up to 300 mg/kg did not result in any obvious adverse effects. This suggests a wide therapeutic window and a low potential for acute toxicity. However, comprehensive toxicological evaluations, including repeated-dose and long-term studies, would be necessary for any clinical development. The compound's excellent safety profile, combined with its potent efficacy, makes it a highly attractive candidate for further research and potential therapeutic applications.
|
| References | |
| Additional Infomation |
AE-3763 is a peptide-based, small-molecule inhibitor of human neutrophil elastase (HNE). Its IUPAC name is 2-(3-(2-(((S)-3-methyl-1-oxo-1-((S)-2-(((S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)carbamoyl)pyrrolidin-1-yl)butan-2-yl)amino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)acetic acid. The compound is distinguished by its potent in vitro activity (IC50 = 29 nM), exceptional water solubility, and stability. It has demonstrated remarkable efficacy in reducing inflammation, tissue damage, and mortality in various in vivo models, including those for lung injury and multiple organ failure. AE-3763 is exclusively a research compound and is not approved for clinical use.
|
| Molecular Formula |
C23H34F3N5O7
|
|---|---|
| Molecular Weight |
549.540576457977
|
| Exact Mass |
549.241
|
| CAS # |
291778-77-3
|
| PubChem CID |
9807572
|
| Appearance |
White to off-white solid powder
|
| LogP |
1.4
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
38
|
| Complexity |
956
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
C1(=O)N(CC(O)=O)CCN1CC(N[C@H](C(N1CCC[C@H]1C(N[C@@H](C(C)C)C(=O)C(F)(F)F)=O)=O)C(C)C)=O
|
| InChi Key |
DHQQXRRWRZFGDW-WBAXXEDZSA-N
|
| InChi Code |
InChI=1S/C23H34F3N5O7/c1-12(2)17(19(35)23(24,25)26)28-20(36)14-6-5-7-31(14)21(37)18(13(3)4)27-15(32)10-29-8-9-30(22(29)38)11-16(33)34/h12-14,17-18H,5-11H2,1-4H3,(H,27,32)(H,28,36)(H,33,34)/t14-,17-,18-/m0/s1
|
| Chemical Name |
2-[3-[2-[[(2S)-3-methyl-1-oxo-1-[(2S)-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]carbamoyl]pyrrolidin-1-yl]butan-2-yl]amino]-2-oxoethyl]-2-oxoimidazolidin-1-yl]acetic acid
|
| 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 |
| 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 : ~16.67 mg/mL (~30.33 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.04 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 16.7 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: ≥ 1.67 mg/mL (3.04 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 16.7 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: ≥ 1.67 mg/mL (3.04 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 | 1.8197 mL | 9.0985 mL | 18.1970 mL | |
| 5 mM | 0.3639 mL | 1.8197 mL | 3.6394 mL | |
| 10 mM | 0.1820 mL | 0.9099 mL | 1.8197 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
