EVP-0015962
EVP-0015962 is an orally active, blood-brain barrier-permeable γ-secretase inhibitor with an IC50 of 3.9 μM. EVP-0015962 alters γ-secretase-mediated cleavage of amyloid precursor protein, reduces Aβ42 production and increases Aβ38 production. EVP-0015962 reduces Aβ aggregates, amyloid plaques and inflammatory markers in the brains of mice, and improves their cognitive impairment. EVP-0015962 can be used for the research of Alzheimer's disease.
For research use only. We do not sell to patients.
- CAS No.: 1447811-26-8
- Formula: C22H19ClF6O3
- Molecular Weight:480.83
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
Biological Activity
Description
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| H4 | IC50 |
67 nM
Compound: EVP-0015962
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Modulation of gamma-secretase in human H4 cells expressing wild type APP751 assessed as inhibition of intracellular amyloid beta 42 production after 16 to 18 hrs by sandwich ELISA
Modulation of gamma-secretase in human H4 cells expressing wild type APP751 assessed as inhibition of intracellular amyloid beta 42 production after 16 to 18 hrs by sandwich ELISA
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[PMID: 26142947] |
In Vitro
EVP-0015962 (0.003-10 μM; 16-18 h) acts as a γ-secretase modulator in H4-APP751 cells, potently decreasing Aβ42 (IC50 = 67 nM) and increasing Aβ38 without altering total Aβ levels at non-cytotoxic concentrations[1].
EVP-0015962 (0.01-30 μM; 24 h) modulates γ-secretase in rat primary neocortical cultures, decreasing Aβ42 (IC50 = 427 nM) and increasing Aβ38 without reducing Aβ1-ₓ levels or inducing cytotoxicity at active concentrations[1].
EVP-0015962 (0.001-100 μM; 3 h) modulates γ-secretase in a cell-free reconstituted system, selectively lowering Aβ42 (IC50 = 3.9 μM) without inhibiting AICD production or altering Aβ40 levels[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
In Vivo
EVP-0015962 (20-60 mg/kg/day; p.o.; continuous via food formulation; 50 weeks) is well-tolerated in male Tg2576 mice, reduces brain Aβ42 levels by 53-89%, aggregated Aβ by 73% at the high dose, amyloid plaque burden, and reactive gliosis, with a dose-dependent trend in efficacy[1].
EVP-0015962 (20-60 mg/kg/day; p.o.; continuous via food formulation; 11 weeks) reverses the contextual fear conditioning cognitive deficit in 30-33-week-old male Tg2576 mice[1].
EVP-0015962 (30 mg/kg; p.o.; single dose) does not reverse the contextual fear conditioning cognitive deficit in 30-week-old male Tg2576 mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Tg2576 (B6;SJL-Tg(APPSWE)2576Kha) (male, 21 weeks old, 24-35 g)[1]
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Dosage:10 mg/kg; 30 mg/kg
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Administration:p.o.; single dose
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Result:Reduced brain Aβ42 levels by 22% relative to vehicle controls (not statistically significant).
Reduced brain Aβ42 levels by 39% relative to vehicle controls.
Left AβTotal levels unchanged with both doses.
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Animal Model:Tg2576 (B6;SJL-Tg(APPSWE)2576Kha) (male, 17-26 weeks old at study start)[1]
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Dosage:20 mg/kg/day; 60 mg/kg/day
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Administration:p.o.; continuous via food formulation; 50 weeks
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Result:Achieved brain concentrations of 2.5 μM (20 mg/kg/day group) and 8.3 μM.
Reduced TBS-soluble Aβ42 by 53% in the 20 mg/kg/day group and 89% in the 60 mg/kg/day group relative to controls.
Reduced formic acid-extractable Aβ42 by 53% in the 20 mg/kg/day group and 86% in the 60 mg/kg group relative to controls.
Increased TBS-soluble Aβ38 by 78% in the 60 mg/kg/day group relative to controls; the 20 mg/kg/day group showed no significant increase.
Reduced formic acid-extractable AβTotal by 49% in the 20 mg/kg/day group and 64% in the 60 mg/kg/day group relative to controls.
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Animal Model:Tg2576 (B6;SJL-Tg(APPSWE)2576Kha) (male, 19-22 weeks old at study start, tested at 30-33 weeks old)[1]
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Dosage:20 mg/kg/day; 60 mg/kg/day
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Administration:p.o.; continuous via food formulation; 11 weeks
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Result:Reversed the cognitive deficit (reduced percent freezing) in Tg2576 mice completely, with percent freezing levels in both treatment groups not significantly different from wild-type controls and significantly higher than control diet Tg2576 mice.
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Animal Model:Tg2576 (B6;SJL-Tg(APPSWE)2576Kha) (male, 30 weeks old)[1]
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Dosage:30 mg/kg
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Administration:p.o.; single dose
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Result:Did not reverse the genotype-associated cognitive deficit (reduced percent freezing) in Tg2576 mice relative to wild-type mice; percent freezing levels in EVP-0015962-treated Tg2576 mice remained significantly lower than those in EVP-0015962-treated wild-type mice.
Chemical Information
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CAS No. 1447811-26-8
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Molecular Weight 480.83
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Formula C22H19ClF6O3
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SMILES
O=C([C@@H](C1=CC(C2=CC=C(C=C2)C(F)(F)F)=C(C(Cl)=C1)OCC(F)(F)F)CC3CCC3)O
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocols
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Notch Pathway Solutions
The Notch pathway is a contact-dependent signaling pathway that controls cell-fate decisions, differentiation, proliferation, and tissue patterning through interactions between membrane-bound Notch receptors and membrane-bound ligands on neighboring cells. Canonical Notch signaling is activated when ligand engagement triggers proteolytic release of the Notch intracellular domain, which enters the nucleus and regulates transcription together with DNA-binding transcriptional complexes. In the canonical mechanism, ligand-dependent Notch activation leads to release of the intracellular Notch domain, and presenilin-dependent γ-secretase activity is required for production of the active intracellular signaling fragment. The released intracellular domain functions as a nuclear signal that converts Notch receptor activation at the membrane into transcriptional regulation of target programs such as HES/HEY-family genes and other context-dependent downstream targets. The literature links Notch p
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Amyloid: Congo Red Amyloid Staining
Congo red amyloid staining is a histochemical method used to detect extracellular amyloid deposits in tissue sections based on the affinity of Congo red dye for β-pleated sheet-rich protein aggregates. When bound to amyloid, Congo red produces characteristic apple-green birefringence under polarized light microscopy, which is widely regarded as a diagnostic feature of amyloid deposition in histopathology. The diagnostic principle relies on the combination of dye binding (congophilia) and optical anisotropy under polarized illumination, which distinguishes amyloid from most non-amyloid eosinophilic extracellular deposits in routine histological evaluation. Amyloid identification by Congo red staining remains a cornerstone in diagnostic pathology despite the availability of adjunct methods such as immunohistochemistry and mass spectrometry, particularly because of its ability to localize deposits directly within tissue architecture. The specificity of Congo red-positive deposits is incre
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Alzheimer’s Disease Modeling
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive functions and loss of specific types of neurons and synapses. Alzheimer's symptoms can be simulated in mice by injecting drugs (such as Aβ) or genetically modified.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)