| Size | Price | Stock | Qty |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg | |||
| Other Sizes |
| Targets |
E2012 targets gamma-secretase, a multi-subunit enzyme complex involved in the cleavage of amyloid precursor protein (APP) and Notch. As a gamma-secretase modulator, it selectively inhibits APP cleavage to amyloid-β (Aβ) over Notch cleavage to Notch intracellular domain (NICD). E2012 also inhibits 3β-hydroxysterol Δ24-reductase (DHCR24), an enzyme in the cholesterol biosynthesis pathway.
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| ln Vitro |
At IC50 values of 11.0 and 15.1 nM, respectively, E2012 has a concentration-dependent inhibitory effect on cholesterol production in primary cultured rat hepatocytes and HepG2 cells [1].
In vitro, E2012 selectively inhibits APP intracellular signaling domain (AICD) cleavage to Aβ over Notch cleavage to NICD at 1 µM in luciferase assays. It inhibits DHCR24 activity in primary rat hepatocytes and HepG2 cells with IC50s of 11 nM and 15 nM, respectively. E2012 reduces Aβ(1-42) production in primary rat embryonic cerebral cortex neurons with an IC50 of 220 nM. |
| ln Vivo |
The in vivo concentrations of E 2012 in the lenses of cataract patients were significantly higher than the in vitro inhibitory effects following 13 weeks of repeated dosage. By blocking DHCR24 at the final stage of cholesterol synthesis, E 2012 causes cataracts in rats. This increases desmosterol in the lens and causes subsequent alterations in desmosterol, which can be used as a predictive safety biomarker for lens opacification [2].
In vivo, E2012 (100 mg/kg) decreases Aβ42 levels in guinea pig brain and cerebral spinal fluid (CSF). Preclinical and early clinical studies demonstrated amyloid-lowering effects in the central nervous system. However, E2012 induces cataract in rats by inhibiting DHCR24, with associated elevation in desmosterol within the lens. Development did not progress to late-stage approval. |
| Enzyme Assay |
In vitro enzyme assays for E2012 measure gamma-secretase activity using cell-based luciferase reporter assays. APP and Notch cleavage are assessed separately to evaluate selectivity. DHCR24 activity is measured in primary rat hepatocytes or HepG2 cells using radiolabeled substrates or mass spectrometry. IC50 values are calculated from dose-response curves. Aβ42 levels are measured by ELISA.
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| Cell Assay |
Cellular assays for E2012 use primary rat embryonic cerebral cortex neurons or cell lines expressing APP. Cells are treated with various concentrations of E2012. Aβ42 levels in culture media are measured by ELISA. DHCR24 inhibition is assessed in hepatocytes by measuring cholesterol and desmosterol levels. Selectivity for APP over Notch cleavage is evaluated.
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| Animal Protocol |
In vivo animal studies for E2012 utilize guinea pig models. The compound is administered orally at 100 mg/kg. Aβ42 levels in brain and CSF are measured by ELISA. Cataract formation is assessed by ophthalmologic examination. Desmosterol levels in the lens are measured as a biomarker for lenticular opacity.
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| ADME/Pharmacokinetics |
E2012 has molecular weight of 419.49 g/mol and molecular formula C25H26FN3O2. It is soluble in DMSO. Purity is ≥95%. It is typically stored at -20°C. Pharmacokinetic properties include oral bioavailability. The compound's development was limited by cataract formation.
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| Toxicity/Toxicokinetics |
Preclinical toxicity of E2012 includes cataract induction in rats due to DHCR24 inhibition. This is associated with elevation in desmosterol within the lens. Desmosterol changes serve as a predictive safety biomarker for lenticular opacity. No other significant toxicities have been reported. The compound was not developed further due to this toxicity.
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| References | |
| Additional Infomation |
E-2012 is a γ-secretase modulator currently being evaluated for its potential as a novel therapy for Alzheimer's disease. Pharmaceutical Indications: It is being investigated for the treatment of Alzheimer's disease. Mechanism of Action: γ-secretase plays a role in the formation of β-amyloid protein, a major component of brain plaques and considered one of the causes of Alzheimer's disease. E-2012 is a novel compound discovered by Eisai that, in preclinical (laboratory) studies, has shown the potential to reduce β-amyloid protein formation by modulating the function of γ-secretase.
E2012 is an experimental gamma-secretase modulator for Alzheimer's disease. It selectively reduces Aβ42 production without affecting Notch processing. It also inhibits DHCR24. Development was discontinued due to cataract formation in rats. It is available for research purposes only. |
| Molecular Formula |
C25H26FN3O2
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|---|---|
| Molecular Weight |
419.5004
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| Exact Mass |
419.201
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| CAS # |
870843-42-8
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| PubChem CID |
11560787
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.195g/cm3
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| Boiling Point |
649.168ºC at 760 mmHg
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| Flash Point |
346.405ºC
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| Index of Refraction |
1.6
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| LogP |
5.033
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
649
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CN(C=N1)C2=C(C=C(C=C2)/C=C/3\CCCN(C3=O)[C@@H](C)C4=CC=C(C=C4)F)OC
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| InChi Key |
PUOAETJYKQITMO-LANLRWRYSA-N
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| InChi Code |
InChI=1S/C25H26FN3O2/c1-17-15-28(16-27-17)23-11-6-19(14-24(23)31-3)13-21-5-4-12-29(25(21)30)18(2)20-7-9-22(26)10-8-20/h6-11,13-16,18H,4-5,12H2,1-3H3/b21-13+/t18-/m0/s1
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| Chemical Name |
(3E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]piperidin-2-one
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| Synonyms |
E 2012 E-2012 E2012
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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 : ≥ 50 mg/mL (~119.19 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.96 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
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 (5.96 mM) 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; 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 (5.96 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 | 2.3838 mL | 11.9190 mL | 23.8379 mL | |
| 5 mM | 0.4768 mL | 2.3838 mL | 4.7676 mL | |
| 10 mM | 0.2384 mL | 1.1919 mL | 2.3838 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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