Cat. No.: HY-10009

Semagacestat

(Synonyms: LY450139)

12 Cited Publications

Customer Review

Based on 12 publication(s) in Google Scholar

Semagacestat is a γ-secretase inhibitor, inhibits β-amyloid (Aβ42), Aβ38 and Aβ40 with IC₅₀s of 10.9, 12 and 12.1 nM, respectively; also inhibits Notch signaling with IC₅₀ of 14.1 nM. Semagacestat can be used for the research of alzheimer's disease.

For research use only. We do not sell to patients.

Purity: 98.61%
CAS No.: 425386-60-3
Formula: C₁₉H₂₇N₃O₄
Molecular Weight:361.44

Storage:

Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 2 years , -20°C, 1 year

Semagacestat Chemical Structure

CAS No.: 425386-60-3

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Fluorescent Dye

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Biological Activity
- Description
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- In Vivo
- Clinical Trial
Chemical Information
Publications (12)
Solvent & Solubility
- In Vitro
- In Vivo
Protocol
Purity & Documentation
References
Help & FAQs
Bioz

Biological Activity

Description

IC₅₀ & Target

IC50: 10.9 nM (Aβ42), 12 nM (Aβ38), 12.1 nM (Aβ40), 14.1 nM (Notch)^[1]

Cellular Effect

Cell Line	Type	Value	Description	References
CHO	EC₅₀	28 nM Compound: LY-450139	Inhibition of gamma-secretase expressed in CHO cells expressing wild type human recombinant APP assessed as amyloid beta40 aggregation Inhibition of gamma-secretase expressed in CHO cells expressing wild type human recombinant APP assessed as amyloid beta40 aggregation	[PMID: 18556202]
CHO	EC₅₀	63 nM Compound: LY-450139	Inhibition of mouse notch expressed in CHO cells assessed as transactivation of soluble alkaline phosphatase reporter system Inhibition of mouse notch expressed in CHO cells assessed as transactivation of soluble alkaline phosphatase reporter system	[PMID: 18556202]
CHO	ED₅₀	15 nM Compound: 41	Inhibition of gamma-secretase in CHO cells assessed expressing APPSw assessed as inhibition of amyloid beta(1 to x) secretion after overnight incubation by ELISA Inhibition of gamma-secretase in CHO cells assessed expressing APPSw assessed as inhibition of amyloid beta(1 to x) secretion after overnight incubation by ELISA	[PMID: 23713656]
CHO	ED₅₀	220 nM Compound: 41	Inhibition of gamma-secretase in CHO cells assessed expressing NotchdeltaE assessed as inhibition of notch cleavage after overnight incubation by luciferase reporter gene assay Inhibition of gamma-secretase in CHO cells assessed expressing NotchdeltaE assessed as inhibition of notch cleavage after overnight incubation by luciferase reporter gene assay	[PMID: 23713656]
SH-SY5Y	IC₅₀	38 nM Compound: 16 LY-450139	Displacement of [3H]5-chloro-N-((2S,3R)-5,5,5-trifluoro-1-hydroxy-3-methylpentan-2-yl)thiophene-2-sulfonamide from gamma secretase in human SH-SY5Y cells by competitive binding assay Displacement of [3H]5-chloro-N-((2S,3R)-5,5,5-trifluoro-1-hydroxy-3-methylpentan-2-yl)thiophene-2-sulfonamide from gamma secretase in human SH-SY5Y cells by competitive binding assay	[PMID: 19694467]
SH-SY5Y	IC₅₀	38 nM Compound: 16 LY-450139	Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells	[PMID: 19694467]

In Vitro

Semagacestat (LY450139) reduces the secretion of Aβ42, Aβ40, and Aβ38 in 96-well-cultured media and increases β-CTF in cell lysates as expected, although this increase is unexpectedly attenuated at high concentrations^[1].
In cortical neurons (CTX), Semagacestat (LY450139) causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC₅₀ value 111 nM for Semagacestat. Semagacestat causes a concentration-dependent decrease in Aβ40 and Aβ42 secreted into the medium with an IC₅₀ value of 126 and 130 nM, respectively^[2].
Semagacestat (3 Μm; for 4 days) exhibits no significant cell toxicity in Huh7 cells^[5].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

In Vivo

Semagacestat (LY450139) is found to decrease both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction;p<0.01) and increase β-CTF at 0.3-10 mg/kg in a dose-dependent manner (15-162% elevation; p<0.01 at 1-10 mg/kg)^[1]. The γ-secretase inhibitor, Semagacestat (LY450139), a highly potent low molecular weight compound, significantly reduces β-amyloid (Aβ) levels in cell cultures permanently over-expressing APP and in both wildtype and transgenic APP-expressing mice. Three hours following p.o. dosing of 30 mg/kg Semagacestat levels of Aβ40 are reduced by 43% (unpaired t-test, p=0.002) in the brains of wildtype C57BL/6 mice compare with vehicle treated controls. Subcutaneous administration of Semagacestat (30 mg/kg) transiently decreases the amounts of Aβ40 in the dialysate with a maximum reduction in Aβ40 levels of 80% at 3 h post-dosing (p<0.001)^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial

NCT Number	Sponsor	Condition	Start Date	Phase A549
NCT01329991	Plexxikon\|		2011-05	PHASE1

Chemical Information

CAS No. 425386-60-3
Appearance Solid
Molecular Weight 361.44
Formula C₁₉H₂₇N₃O₄
Color White to off-white
SMILES

O=C([C@H]1NC([C@@H](NC([C@H](C(C)C)O)=O)C)=O)N(CCC2=C1C=CC=C2)C
Synonyms

LY450139
Shipping

Room temperature in continental US; may vary elsewhere.

Storage

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	2 years
	-20°C	1 year

Publications (12)

All WB

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Journal Impact Factor

EMBO Mol Med

γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. [Abstract]

2017 Jul;9(7):950-966. PMID: 28539479

Semagacestat purchased from MedChemExpress. Usage Cited in: EMBO Mol Med. 2017 Jul;9(7):950-966. [Abstract]

Turnover of endogenous CD74 P8 is inhibited by RO4929079 and BMS-906024. Cell lysate Western blot of A20 cells treated with GSIs is developed with In-1 antibody. MK-0752 and Semagacestat tests used the same control lane (0 nM).
EMBO J

The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. [Abstract]

2012 May 16;31(10):2261-74. PMID: 22505025
Cell Syst

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations. [Abstract]

2018 Apr 25;6(4):424-443.e7. PMID: 29655704
Molecules

New flurbiprofen derivatives: synthesis, membrane affinity and evaluation of in vitro effect on β-amyloid levels. [Abstract]

2013 Sep 3;18(9):10747-67. PMID: 24005968
J Neurosci

Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. [Abstract]

2015 Feb 11;35(6):2612-23. PMID: 25673853
J Biol Chem

Individual and combined presenilin 1 and 2 knockouts reveal that both have highly overlapping functions in HEK293T cells. [Abstract]

2019 Jul 19;294(29):11276-11285. PMID: 31167792
J Alzheimers Dis

A canine model to evaluate efficacy and safety of γ-secretase inhibitors and modulators. [Abstract]

2012;28(4):809-22. PMID: 22072214
J Alzheimers Dis

Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. [Abstract]

2010;21(3):1005-12. PMID: 20634579
Biochem Biophys Res Commun

Utility of human induced pluripotent stem cell-derived small intestinal epithelial cells for pharmacokinetic, toxicological, and immunological studies. [Abstract]

2024 Jan 15:692:149356. PMID: 38071890
Neurol Res

The long-non-coding RNA NEAT1 is a novel target for Alzheimer's disease progression via miR-124/BACE1 axis. [Abstract]

2019 Jun;41(6):489-497. PMID: 31014193
Weill Medical College of Cornell University

2026.
ACS Comb Sci

Benzimidazolyl-pyrazolo[3,4- b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest. [Abstract]

2019 Dec 9;21(12):805-816. PMID: 31689077

Solvent & Solubility

In Vitro:

DMSO : ≥ 100 mg/mL (276.67 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

* "≥" means soluble, but saturation unknown.

View the Complete Stock Solution Preparation Table

Preparing Stock Solutions

View the Complete Stock Solution Preparation Table

Concentration Solvent Mass

1 mg

5 mg

10 mg

Concentration

Solvent

Mass

1 mM

2.7667 mL

13.8336 mL

27.6671 mL

5 mM

0.5533 mL

2.7667 mL

5.5334 mL

10 mM

0.2767 mL

1.3834 mL

2.7667 mL

Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.

Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

Molarity Calculator

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass Mass

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Molecular Weight Molecular Weight

Dilution Calculator

Concentration _(start) × Volume _(start) = Concentration _(final) × Volume _(final)

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In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

Stock Solution Working Solution

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

Protocol 1

Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline

Solubility: ≥ 3 mg/mL (8.30 mM); Clear solution

This protocol yields a clear solution of ≥ 3 mg/mL (saturation unknown).

Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (30.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

Protocol 2

Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)

Solubility: ≥ 3 mg/mL (8.30 mM); Clear solution

This protocol yields a clear solution of ≥ 3 mg/mL (saturation unknown).

Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (30.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

Protocol 3

Add each solvent one by one: 10% DMSO 90% Corn Oil

Solubility: ≥ 3 mg/mL (8.30 mM); Clear solution

This protocol yields a clear solution of ≥ 3 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.

Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (30.0 mg/mL) to 900 μL Corn oil, and mix evenly.

In Vivo Dissolution Calculator

Please enter the basic information of animal experiments:

Dosage Dosage
mg/kg
Animal Weight (Per Animal) Animal Weight (Per Animal)
g
Dosing Volume (Per Animal) Dosing Volume (Per Animal)
μL
Number of Animals Number of Animals

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.

Please enter your animal formula composition:

%
DMSO +

Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
%
+
+
%
Tween-80 + +
%
Saline +

The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).

Working solution concentration: 0.22 mg/mL

Protocol

Kinase Assay^[1]

H4 human glioma cells stably overexpressing human wild-type APP695 are maintained in DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin. Cells are cultured in 96- or 6-well plates overnight, and then treated with each drug (e.g., Semagacestat) at various concentrations for 24 h. Levels of Aβ1-42, Aβ1-40, and Aβ1-38 in the media are measured using separate ELISA kits. To quantify β-CTF, cells are lysed with RIPA buffer (25 mM Tris, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS; pH 7.6) containing Complete protease inhibitor mixture and applied to a human β-CTF ELISA kit at 1:20 dilution. Aliquots of the cell lysate are also used for CellTiter-Glo Luminescent Cell Viability Assay. The cell lysate from the six-well plate is subjected to Western blot analysis^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay^[2]

Murine cortical neurons (CTX) are isolated from day 14 to 16 foetal C57BL/6 mice. Briefly, dissociated neurons are plated on 100 μg/mL poly-L-lysine coated dishes at a density of 0.25×10⁶ cells/cm² (800000 cells/mL; 100 μL/well, 96-well plate) and cultured in Neurobasal medium supplemented with 2% B-27 supplement without antioxidants, 0.5 mM L-glutamine and 100 U/mL penicillin and 0.1 mg/mL streptomycin. Neurons are fed every third day by replacing half of the medium. The proportion of glia cells in the cultures is less than 10%, as assessed by an antibody against glia-fibrillary acidic protein. CTX are used at 6 days in vitro (DIV) after complete medium change and incubated with secretase inhibitors (e.g., Semagacestat) for 24 h. Neurons and cell medium are used at DIV 7. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce MTT following incubation with 0.5 mg/mL MTT for 60 min. Viability is routinely measured after all in vitro pharmacological experiments^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration^[1]

Mice^[1]
Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L) are used. Male transgenic mice are procured and crossbred with female B6SJLF1/J mice. To identify drug effects on cognitive function, four different experiments are conducted. The objective of Experiment 1 is to elucidate acute and subchronic drug effects on cognitive deficits in Tg2576 mice. Each drug (Semagacestat, BMS-708163, and GSM-2) is orally administered to 5.5-month-old Tg2576 mice for 8 d. Y-maze tests are conducted to evaluate spatial working memory 3 h after administration on days 1 and 8. Vehicle-treated Tg2576 mice demonstrates significantly lower spontaneous alternation rates than WT mice in the Y-maze test, suggesting deficits in spatial working memory. On day 1, 1 mg/kg Semagacestat, 1 mg/kg BMS-708163, and 0.1-0.3 mg/kg GSM-2 significantly ameliorates these cognitive deficits (acute effects). On day 8, however, the GSI effects disappear, whereas GSM-2 retained its significant effects (subchronic effects). Mice are killed immediately after the Y-maze test on day 8, when hippocampal levels of Aβ42, Aβ40, and β-CTF are determined by ELISA.

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Purity & Documentation

Select Batch:

Purity: 99.98%

Assay: 99.98%

ee.: 99.98%

Data Sheet (284 KB)
SDS (393 KB)
- English - EN (393 KB)
- Français - FR (393 KB)
- Deutsch - DE (393 KB)
- Norwegian - NO (393 KB)
- Español - ES (393 KB)
- Swedish - SV (393 KB)
- Italian - IT (393 KB)
- Portuguese - PT (393 KB)
COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Handling Instructions (2659 KB)

References

[1]. Mitani Y, et al. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci. 2012 Feb 8;32(6):2037-50. [Content Brief]

[2]. Elvang AB, et al. Differential effects of gamma-secretase and BACE1 inhibition on brain Abeta levels in vitro and in vivo. J Neurochem. 2009 Sep;110(5):1377-87. [Content Brief]

[3]. Justice NJ, et al. Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. J Neurosci. 2015 Feb 11;35(6):2612-23. [Content Brief]

[4]. Portelius E, et al. Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. J Alzheimers Dis. 2010;21(3):1005-12. [Content Brief]

[5]. Junki Hirano, et al. Characterization of SPP inhibitors suppressing propagation of HCV and protozoa. Proc Natl Acad Sci U S A. 2017 Dec12;114(50):E10782-E10791. [Content Brief]

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

Complete Stock Solution Preparation Table

Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

Optional Solvent	Concentration Solvent Mass	1 mg	5 mg	10 mg	25 mg
DMSO	1 mM	2.7667 mL	13.8336 mL	27.6671 mL	69.1678 mL
	5 mM	0.5533 mL	2.7667 mL	5.5334 mL	13.8336 mL
	10 mM	0.2767 mL	1.3834 mL	2.7667 mL	6.9168 mL
	15 mM	0.1844 mL	0.9222 mL	1.8445 mL	4.6112 mL
	20 mM	0.1383 mL	0.6917 mL	1.3834 mL	3.4584 mL
	25 mM	0.1107 mL	0.5533 mL	1.1067 mL	2.7667 mL
	30 mM	0.0922 mL	0.4611 mL	0.9222 mL	2.3056 mL
	40 mM	0.0692 mL	0.3458 mL	0.6917 mL	1.7292 mL
	50 mM	0.0553 mL	0.2767 mL	0.5533 mL	1.3834 mL
	60 mM	0.0461 mL	0.2306 mL	0.4611 mL	1.1528 mL
	80 mM	0.0346 mL	0.1729 mL	0.3458 mL	0.8646 mL
	100 mM	0.0277 mL	0.1383 mL	0.2767 mL	0.6917 mL

Keywords

Semagacestat

12 Cited Publications

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Semagacestat

Neuronal Signaling Compound Library

Stem Cell Signaling Compound Library

Wnt/Hedgehog/Notch Compound Library

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Mass Spectrometry Human Metabolite Library

Publications Citing Use of MedChemExpress (MCE) Semagacestat

Biological Activity

Chemical Information

Publications (12)

Solvent & Solubility

Protocol

Purity & Documentation

References

Help & FAQs

Complete Stock Solution Preparation Table

Semagacestat Related Classifications

Cat. No.: HY-10009