Semagacestat

SKU: orb1301052

Description

Semagacestat (LY450139) is a potent γ-secretase inhibitor that reduces Aβ peptide production (Aβ42/Aβ40/Aβ38) and inhibits Notch signaling with nanomolar IC50 values. It has been utilized in both in vitro and in vivo research models to investigate Alzheimer's disease pathology and Notch-related cellular processes.

Research Area

Neuroscience, Protein Biochemistry, Stem Cell & Developmental Biology

Key Properties

• CAS Number: 425386-60-3
• MW: 361.44
• Purity: 99.90% (May vary between batches)
• Formula: C₁₉H₂₇N₃O₄
• SMILES: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N[C@H]1c2ccccc2CCN(C)C1=O
• Target: Gamma-secretase,Beta Amyloid
• Solubility: 10% DMSO+40% PEG300+5% Tween 80+45% Saline:2.5 mg/mL (6.92 mM);H2O:< 1 mg/mL (insoluble or slightly soluble);DMSO:67 mg/mL (185.37 mM);Ethanol:39 mg/mL (107.9 mM)

Bioactivity

• Target IC50:
  γ-secretase (Aβ38):12.0 nM|γ-secretase (Aβ42):10.9 nM|γ-secretase (Aβ40):12.1 nM
• In Vivo:
  Oral administration of Semagacestat (1 mg/kg) to 5.5-month old APP-transgenic Tg2576 mice significantly ameliorates memory deficits on spatial working memory using the Y-maze task, which disappears after 8 days subchronic dosing. LY450139 decreases hippocampal levels of both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction) and increases β-CTF at 0.3-10 mg/kg in a dose dependent manner with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin or EphA4, in the brain, but impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice failing to restore cognitive deficits in the Y-maze test.
• In Vitro:
  Semagacestat reduces the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium, with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively, without affecting cell viability. Semagacestat also increases β-CTF in cell lysates with ECmax of 16.0 nM, and the increase can be unexpectedly attenuated at high concentrations. Semagacestat inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/Aβ42 IC50 only 1.3. Semagacestat causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 of 111 nM from murine CTX expressing endogenous murine APP, but murine Aβ42 formation in CTX is roughly 12-fold less than Aβ40 in accordance with data for neurons from wild type mice.
• Cell Research:
  Cells are incubated with Semagacestat for 24 hours. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) following incubation with 0.5 mg/mL MTT for 60 minutes. For the detection of sAPP species, cells are lysed and analysed by western blotting.(Only for Reference)

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

BetaAmyloid, Beta Amyloid, Amyloid-β, bAmyloid, b Amyloid, Abeta, LY 450139, LY450139, LY-450139, inhibit, Inhibitor, Notch, Gammasecretase, Gamma secretase, Semagacestat, β Amyloid, βAmyloid, β-amyloid peptide, γ secretase(Aβ42), γ secretase(Aβ38), γ secretase(Aβ40), γ-secretase

Compound Identifiers

PubChem CID

9843750