Semagacestat (LY450139)

Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM. Phase 3.

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Semagacestat (LY450139) Chemical Structure

Semagacestat (LY450139) Chemical Structure
Molecular Weight: 361.44

Validation & Quality Control

Customer Reviews(2)

Quality Control & MSDS

Related Compound Libraries

Semagacestat (LY450139) is available in the following compound libraries:

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Product Information

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  • Research Area

Product Description

Biological Activity

Description Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM. Phase 3.
Targets γ secretase(Aβ42) [1] γ secretase(Aβ38) [1] γ secretase(Aβ40) [1] Notch [1]
IC50 10.9 nM 12.0 nM 12.1 nM 14.1 nM
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. [1] 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. [2]
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. [1]
Features The best characterized γ-secretase inhibitor that has reached the clinic.

Protocol(Only for Reference)

Kinase Assay: [1]

Cellular APP processing assay and Notch signaling assay H4 human glioma cells stably overexpressing human wild-type APP695 are treated with Semagacestat at various concentrations for 24 hours. Levels of Aβ42, Aβ40, and Aβ38 in the media are measured using separate ELISA kits. The expression vector of the constitutively active form of Notch (NotchΔE), encoding bases 1-60 and 5193-6657 of the human Notch1 coding region (NM_017617), is constructed into a pcDNA3.1 vector with a sequence modification from mouse to human. Notch signaling activity is evaluated using Cignal RBP-Jk Reporter Assay kit. RBP-Jk protein [CSL/CBF1/Su(H)/Lag1] is a transcription factor activated with Notch intracellular domain produced by γ-secretase. H4 cells are transiently transfected with the human NotchΔE expression vector and the RBP-Jk-responsive luciferase construct using Lipofectamine 2000, and then exposed to various concentrations of Semagacestat for 16 hours. Notch signaling is measured based on luciferase activity in the cell lysate using the Dual-Glo Luciferase Assay System.

Cell Assay: [2]

Cell lines Murine cortical neurons and cerebellar granule cells
Concentrations Dissolved in DMSO, final concentration ~10 μM
Incubation Time 24 hours
Method 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.

Animal Study: [1]

Animal Models Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L)
Formulation Dissolved in 0.5% methyl cellulose.
Dosages ~30 mg/kg
Administration Orally administered once daily
Solubility 0.5% methylcellulose, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Mitani Y, et al. J Neurosci, 2012, 32(6), 2037-2050.

[2] Elvang AB, et al. J Neurochem, 2009, 110(5), 1377-1387.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-13)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01035138 Completed Alzheimers Disease Eli Lilly and Company December 2009 Phase 3
NCT00762411 Completed Alzheimers Disease Eli Lilly and Company September 2008 Phase 3
NCT00594568 Completed Alzheimers Disease Eli Lilly and Company March 2008 Phase 3
NCT00765115 Completed Alzheimer Disease Eli Lilly and Company July 2006 Phase 1
NCT00244322 Completed Alzheimers Disease Eli Lilly and Company October 2005 Phase 2

Chemical Information

Download Semagacestat (LY450139) SDF
Molecular Weight (MW) 361.44
Formula

C19H27N3O4

CAS No. 425386-60-3
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 72 mg/mL (199 mM)
Water <1 mg/mL (<1 mM)
Ethanol 41 mg/mL (113 mM)
In vivo 0.5% methylcellulose, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (S)-2-hydroxy-3-methyl-N-((S)-1-((S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ylamino)-1-oxopropan-2-yl)butanamide

Research Area

Customer Reviews (2)


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Rating
Source J Biol Chem, 2012, 287(15):11810-9. Semagacestat (LY450139) purchased from Selleck
Method cellular assay
Cell Lines HEK293 cells
Concentrations
Incubation Time 5 h
Results Semagacestat inhibited NICD translocation with high potency.

Click to enlarge
Rating
Source J Biol Chem, 2014, 289(3):1540-50. Semagacestat (LY450139) purchased from Selleck
Method subsequent MSD and LC-MS analysis
Cell Lines HEK cells
Concentrations 1 uM
Incubation Time 19 h
Results HEK/APPswe cells were either left non-treated (-) or exposed to the γ-secretase inhibitor (GSI) semagacestat (+) for 19 h prior to cell harvesting and membrane preparation (Substrate accumulation). Exposure of cells with GSI prior to membrane preparation results in higher Aβ1-42 and Aβx-42 signals as compared to membranes derived from non-GSI treated cells. Direct addition of semagacestat to the membranes in the novo Aβ production assay inhibited Aβ production (Semagacestat (1 µM)). The amount of Aβx-42 is higher than Aβ1-42 suggesting that C83 is the major substrate for the Aβ42 signal detected.

Product Citations (2)

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