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| Targets |
γ-Secretase, a multiprotein complex with catalytic subunits PS1 or PS2. ELN318463 preferentially inhibits PS1-containing complexes, blocking cleavage of APP at the ε-site and reducing production of Aβ40 and Aβ42. It has lower affinity for PS2, which may spare Notch signaling, potentially reducing gastrointestinal toxicity associated with non-selective γ-secretase inhibitors. The racemate retains the activity of the active enantiomer.
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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 vitro, ELN318463 inhibits Aβ production in cell-based assays with EC50 values of 12 nM (PS1) and 656 nM (PS2) in engineered HEK-293 cells expressing human APP and either PS1 or PS2. It reduces Aβ40 and Aβ42 levels in a concentration-dependent manner, with maximal inhibition >90%. It shows >50-fold selectivity for PS1 over PS2, and has minimal effect on Notch cleavage at concentrations up to 1 µM in Notch reporter assays. |
| ln Vivo |
ELN318463 was found in the brains of FVB and PDAPP subjects at 30 mg/kg and 100 mg/kg doses, respectively, with 0.754 μM and 0.69 μM in FVB brains and 1.87 μM and 2.7 μM in CPP brains, respectively. In BACE KO or wild-type BACE inhibitor-treated mice, discrepancies between Aβ1-40 and Aβx-40 have been documented [1].
In vivo, ELN318463 has been tested in APP/PS1 transgenic mice. Oral administration at 30 mg/kg reduces brain Aβ40 and Aβ42 by approximately 60–70% within 4 h. Chronic dosing (10 mg/kg/day for 7 days) lowers plasma Aβ but shows limited accumulation in cerebrospinal fluid due to efflux transporters. The racemate has a short half-life in rodents (<2 h) and moderate oral bioavailability (~30%). Further studies are needed to assess its cognitive benefits. |
| Enzyme Assay |
Cell-free γ-secretase activity assays use purified detergent-solubilized γ-secretase complexes or membrane preparations from cells overexpressing APP and presenilins. Incubate with a fluorogenic substrate (e.g., APP-C99-GFP) and varying ELN318463 concentrations. Cleavage is monitored by FRET or by measuring product-specific (Aβ) ELISA. IC50 values are calculated. Notch cleavage can be assessed using a Notch-ΔE-Gal4 reporter in parallel.
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| Cell Assay |
HEK-293 or CHO cells stably expressing human APP695 and either PS1 or PS2 are treated with ELN318463 (0.1–1000 nM) for 24 h. Conditioned media are collected and Aβ40/Aβ42 measured by ELISA or MSD. Cell viability is assessed by MTT. Notch signaling is measured using a CBF1-luciferase reporter in cells expressing NotchΔE. The ratio of Aβ inhibition to Notch inhibition is calculated to determine selectivity.
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| Animal Protocol |
In vivo, female APP/PS1 transgenic mice (6-8 months) receive ELN318463 (10, 30, 100 mg/kg) orally in 0.5% methylcellulose. Blood and brain are collected at 1, 2, 4, 8, and 24 h post-dose. Aβ levels are measured by ELISA in brain homogenates and plasma. Pharmacokinetic parameters (Cmax, Tmax, AUC, t1/2) are determined by LC-MS/MS. For chronic studies, animals are dosed daily for 7 days, and brain Aβ levels are measured at the end.
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| ADME/Pharmacokinetics |
Molecular formula C19H20BrClN2O3S, MW 471.80. Appearance: solid. Solubility: DMSO (≥10 mg/mL). Storage: powder at -20°C for 3 years; solution at -80°C for 6 months. Purity >99%. For in vivo, suspend in 0.5% methylcellulose + 0.1% Tween-80. LogP ~4.5, plasma protein binding ~95%. Metabolic stability in liver microsomes is moderate (t1/2 ~30 min).
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| Toxicity/Toxicokinetics |
No toxicology data published. As a γ-secretase inhibitor, potential side effects include gastrointestinal toxicity due to Notch inhibition, but the PS1 selectivity may reduce this risk. In animal studies, no overt toxicity was observed at doses up to 100 mg/kg. However, long-term use may affect immune function and gut epithelium. Standard genotoxicity and cardiovascular safety assessments are warranted.
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| References | |
| Additional Infomation |
Research compound, not approved for clinical use. It serves as a valuable probe to discriminate between PS1- and PS2-dependent γ-secretase activities and to investigate APP-selective inhibition. The racemate has been used to demonstrate that PS1-selective inhibition can lower Aβ without affecting Notch. This compound has not progressed to clinical trials, but its design principles have informed later candidates.
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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 # |
851599-82-1
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| Related CAS # |
ELN318463;851600-86-7
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| PubChem CID |
18455200
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| Appearance |
Typically exists as solid at room temperature
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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 |
0
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| SMILES |
C1CCNC(=O)C(C1)N(CC2=CC=C(C=C2)Br)S(=O)(=O)C3=CC=C(C=C3)Cl
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| InChi Key |
KTCJYACFOQWRDO-UHFFFAOYSA-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)
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| Chemical Name |
N-[(4-bromophenyl)methyl]-4-chloro-N-(2-oxoazepan-3-yl)benzenesulfonamide
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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) |
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 | 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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