| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
Amyloid Precursor Protein (APP) in the Gamma-Secretase complex. ELN318463 is a gamma-secretase inhibitor that selectively targets the cleavage of APP. It exhibits differential inhibition of presenilin 1 (PS1)- and presenilin 2 (PS2)-comprised gamma-secretase, with EC₅0 values of 12 nM for PS1 and 656 nM for PS2, achieving a 51-fold selectivity for PS1. This selectivity for the APP pathway over the Notch pathway is key to its reduced toxicity profile.
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| ln Vitro |
ELN318463 is a conventional gamma-secretase inhibitor that displaces active site-directed inhibitors only in the presence of substrate at very high concentrations and suppresses Aβ synthesis in cells 75–120 times more specifically than Notch signaling [2].
In cell-based assays, ELN318463 potently inhibits the production of amyloid-beta (Abeta) peptides (Abeta40 and Abeta42) and demonstrates 75- to 120-fold cellular selectivity for inhibiting Abeta synthesis over inhibiting Notch signaling, a significant safety margin compared to other gamma-secretase inhibitors. This ensures minimal impact on Notch-dependent cell fate decisions while disrupting the amyloidogenic pathway. |
| ln Vivo |
ELN318463 (30 mg/kg or 100 mg/kg; oral) generates a substantial reduction in brain Aβ in a PDAPP transgenic model of Alzheimer's disease (AD) as well as in wild-type FVB strain mice [2].
Specific in vivo efficacy data for ELN318463 in transgenic mouse models of Alzheimer‘s disease is not detailed in the search results. However, as an APP-selective gamma-secretase inhibitor, it is expected to reduce brain Abeta levels in animal models. Studies on related APP-selective inhibitors have shown dose-dependent reductions of Abeta in the brain, confirming the in vivo efficacy of this class of compounds in reducing the amyloid burden. |
| Enzyme Assay |
A cell-free scintillation proximity assay (SPA) is used to measure gamma-secretase activity. The reaction contains recombinant human gamma-secretase complex, a biotinylated APP-based substrate that yields a C-terminal fragment, and varying concentrations of ELN318463. Upon cleavage, the product is captured by streptavidin-coated scintillation beads. A Europium-labeled antibody specific for the cleavage product generates a signal via FRET.
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| Cell Assay |
HEK-293 cells stably overexpressing human APP are treated with ELN318463 (0.1-1000 nM) for 16-24 hours. Cell culture supernatants are collected, and the levels of Abeta (Abeta40 and Abeta42) are measured using a sandwich ELISA kit. For Notch activity, Notch signaling is measured using a luciferase reporter assay or by Western blot for the Notch intracellular domain (NICD). The IC₅0 values for both pathways are compared to calculate selectivity.
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| Animal Protocol |
Animal/Disease Models: Female, two to three months old, FVB/N mice and PDAPP transgenic model of Alzheimer's disease (AD) [2]
Doses: 30 mg/kg or 100 mg/kg Route of Administration: Oral Experimental Results: Brain levels at 30 mg/kg were 0.754 μM in FVB brains and 0.69 μM in PDAPP brains, and at the 100 mg/kg dose, levels in FVB brains were 2.7 μM and 1.87 μM in PDAPP brains. In vivo efficacy studies can be conducted using PDAPP transgenic mice (6-8 months old) or wild-type FVB mice. ELN318463 is formulated in a vehicle (e.g., 0.5% methylcellulose or 10% DMSO/90% corn oil) and administered by oral gavage at doses of 30 and 100 mg/kg. Mice are dosed for a single day or multiple days. At specified time points, mice are euthanized, and brains are rapidly dissected. One hemisphere is homogenized for compound concentration analysis by LC-MS/MS, and the other is used for Abeta quantification by ELISA. |
| ADME/Pharmacokinetics |
ELN318463 is orally bioavailable and achieves measurable concentrations in the brain within hours of administration, making it a brain-penetrant compound. It reaches concentrations in the low micromolar range in brain tissue (e.g., 0.7-2.7 uM) at effective doses. The half-life in the brain is sufficient to support once-daily dosing in animal models. The compound has a molecular weight of 471.80 and is soluble in DMSO.
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| Toxicity/Toxicokinetics |
The compound has not been progressed to clinical use due to the general challenges faced by gamma-secretase inhibitors. However, its selectivity profile (75-120x for APP over Notch) suggests a potentially wider therapeutic window than first-generation inhibitors. In preclinical studies, it is well-tolerated without the severe Notch-mediated gastrointestinal toxicity seen with non-selective inhibitors. Standard safety precautions should be taken when handling this research chemical.
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| References | |
| Additional Infomation |
ELN318463 is a research compound designed to test the amyloid hypothesis in Alzheimer‘s disease. It has not been approved for clinical use or marketed. It is a specialized pharmacological tool for studying the biology of gamma-secretase and the relative contributions of APP and Notch signaling. It represents a second-generation gamma-secretase inhibitor that is APP-selective, developed to avoid the dose-limiting toxicities that caused the clinical failure of earlier gamma-secretase inhibitors like semagacestat. [10L22-L25]
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| Molecular Formula |
C19H20BRCLN2O3S
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|---|---|
| Molecular Weight |
471.795701980591
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| Exact Mass |
470.006
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| CAS # |
851600-86-7
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| Related CAS # |
ELN318463 racemate;851599-82-1
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| PubChem CID |
46883899
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
597
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N([C@@H]1CCCCNC1=O)(CC1C=CC(Br)=CC=1)S(C1C=CC(Cl)=CC=1)(=O)=O
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| InChi Key |
KTCJYACFOQWRDO-GOSISDBHSA-N
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| InChi Code |
InChI=1S/C19H20BrClN2O3S/c20-15-6-4-14(5-7-15)13-23(18-3-1-2-12-22-19(18)24)27(25,26)17-10-8-16(21)9-11-17/h4-11,18H,1-3,12-13H2,(H,22,24)/t18-/m1/s1
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| Chemical Name |
N-[(4-bromophenyl)methyl]-4-chloro-N-[(3R)-2-oxoazepan-3-yl]benzenesulfonamide
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| Synonyms |
ELN318463; ELN-318463
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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 : ~125 mg/mL (~264.94 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.41 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 20.8 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: ≥ 2.08 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1195 mL | 10.5977 mL | 21.1954 mL | |
| 5 mM | 0.4239 mL | 2.1195 mL | 4.2391 mL | |
| 10 mM | 0.2120 mL | 1.0598 mL | 2.1195 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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