Name: Semagacestat (LY450139)
Brand: Selleck Chemicals
SKU: S1594
Availability: InStock
Rating: 5 (22 reviews)

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Quality Control

Batch: Purity: 99.96%

99.96

Related Targets	HDAC Caspase Proteasome MMP HCV Protease Cysteine Protease DPP Tyrosinase HIV Protease Serine Protease
Other Secretase Inhibitors	DAPT LY411575 Nirogacestat (PF-03084014) RO4929097 (RG-4733) DBZ (Dibenzazepine) Avagacestat (BMS-708163) MK-0752 MDL-28170 L-685,458 Itanapraced (CHF 5074)

Cell Culture, Treatment & Working Concentration

Cell Lines	Assay Type	Activity Description
CHO cells	Function assay	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, ED50=0.015 μM
human SH-SY5Y cells	Function assay	Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells, IC50=0.038 μM
African green monkey CV1 cells	Function assay	Inhibition of gamma-secretase expressed in african green monkey CV1 cells coexpressing Gal4 DNA-binding/transactivation domain assessed as inhibition of notch processing by luciferase reporter assay, IC50=0.31623 μM
Click to View More Cell Line Experimental Data

Solubility

In vitro
Batch:

DMSO : 73 mg/mL (201.96 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 41 mg/mL

Water : Insoluble

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
Mass value Mass unit	Concentration value Concentration unit	Volume value Volume unit	Molecular weight (g/mol)

Dilution Calculator Molecular Weight Calculator

In vivo batch selection In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	0.5% methylcellulose Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	10.000mg/ml (27.67mM)	Taking the 1 mL working solution as an example, take 10 mg of this product, add it to 1 ml of 0.5% methylcellulose clear solution, and mix evenly to form a uniform suspension. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg

Average weight of animals: g

Dosing volume per animal: μL

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Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO

%

% Tween 80

% ddH₂O

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Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Chemical Information, Storage & Stability

Molecular Weight	361.44	Formula	C₁₉H₂₇N₃O₄	Storage (From the date of receipt)	3 years-20°Cpowder
CAS No.	425386-60-3	Download SDF		Storage of Stock Solutions	1 year-80°Cin solvent 1 month-20°Cin solvent
Synonyms	N/A			Smiles	CC(C)C(C(=O)NC(C)C(=O)NC1C2=CC=CC=C2CCN(C1=O)C)O

Mechanism of Action

Features	The best characterized γ-secretase inhibitor that has reached the clinic.
Targets/IC₅₀/Ki	Aβ42 (H4 human glioma cells) 10.9 nM Aβ38 (H4 human glioma cells) 12.0 nM Aβ40 (H4 human glioma cells) 12.1 nM Notch (H4 human glioma cells) 14.1 nM
In vitro	Semagacestat (LY450139) 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. It also increases β-CTF in cell lysates with EC_max of 16.0 nM, and the increase can be unexpectedly attenuated at high concentrations. This compound inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/Aβ42 IC50 only 1.3. It 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.
Kinase Assay	Cellular APP processing assay and Notch signaling assay
Kinase Assay	H4 human glioma cells stably overexpressing human wild-type APP695 are treated with Semagacestat (LY450139) 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 this compound for 16 hours. Notch signaling is measured based on luciferase activity in the cell lysate using the Dual-Glo Luciferase Assay System.
In vivo	Oral administration of Semagacestat (LY450139) (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. It 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.
References	[1] https://pubmed.ncbi.nlm.nih.gov/22323718/ [2] https://pubmed.ncbi.nlm.nih.gov/19519664/

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

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

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Semagacestat (LY450139) Secretase inhibitor

Chemical Structure

Molecular Weight: 361.44