Art. -Nr.: HY-50845

Avagacestat

(Synonyms: BMS-708163)

2 Cited Publications

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Based on 2 publication(s) in Google Scholar

Avagacestat (BMS-708163) is a potent inhibitor of γ-secretase, with IC₅₀s of 0.27 nM and 0.30 nM for Aβ42 and Aβ40 inhibition; Avagacestat (BMS-708163) also inhibits NICD (Notch IntraCellular Domain) with IC₅₀ of 0.84 nM and shows weak inhibition of CYP2C19, with IC₅₀ of 20 μM. Avagacestat can be used for Alzheimer disease research.

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Reinheit: 99.92%
CAS. Nr.: 1146699-66-2
Formel: C₂₀H₁₇ClF₄N₄O₄S
Molecular Weight:520.89

Speicherung:

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

Avagacestat Chemical Structure

CAS. Nr.: 1146699-66-2

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Biologische Aktivität
- Beschreibung
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- In Vivo
- Clinical Trial
Chemical Information
Publications (2)
Lösungsmittel & Löslichkeit
- In Vitro
- In Vivo
Protokoll
Reinheit & Dokumentation
Verweise
Help & FAQs
Classifications
Bioz

Biologische Aktivität

Beschreibung

IC₅₀ & Target

IC50: 0.27 nM (γ-secretase, Aβ42), 0.30 nM (γ-secretase, Aβ40), 20 μM (CYP2C19)^[1], 0.84 nM (NICD)^[2]

Cellular Effect

Cell Line	Type	Value	Description	References
CHO	ED₅₀	1.2 nM Compound: 43	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	71 nM Compound: 43	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]
CHO	IC₅₀	71 nM Compound: BMS-708163	Inhibition of gamma-secretase in CHO cells after overnight incubation by luciferase reporter gene assay Inhibition of gamma-secretase in CHO cells after overnight incubation by luciferase reporter gene assay	[PMID: 23312944]
H4	IC₅₀	0.225 nM Compound: 1, BMS-708163	Inhibition of gamma secretase-mediated amyloid beta42 production in human H4 cells expressing human APP swedish mutant Inhibition of gamma secretase-mediated amyloid beta42 production in human H4 cells expressing human APP swedish mutant	[PMID: 22420884]
H4	IC₅₀	300 pM Compound: 80 BMS-708163	Inhibition of human gamma secretase-mediated amyloid beta (1 to 40) production expressed in human H4 cells Inhibition of human gamma secretase-mediated amyloid beta (1 to 40) production expressed in human H4 cells	[PMID: 19694467]
HEK293	ED₅₀	1.2 nM Compound: BMS-708163	Inhibition of gamma-secretase in HEK293 cells after overnight incubation by Western blotting analysis Inhibition of gamma-secretase in HEK293 cells after overnight incubation by Western blotting analysis	[PMID: 23312944]
IMR-32	IC₅₀	0.13 nM Compound: BMS-708163	Inhibition of gamma-secretase in human IMR32 cell membrane using APP as substrate after 2 hrs by ELISA Inhibition of gamma-secretase in human IMR32 cell membrane using APP as substrate after 2 hrs by ELISA	[PMID: 23312944]
IMR-32	IC₅₀	1.5 nM Compound: BMS-708163	Inhibition of gamma-secretase in human IMR32 cell membrane using Notch as substrate after 2 hrs by ELISA Inhibition of gamma-secretase in human IMR32 cell membrane using Notch as substrate after 2 hrs by ELISA	[PMID: 23312944]

In Vitro

Avagacestat (BMS-708163) exhibits weaker potency for inhibition of Notch processing, IC₅₀=58±23 nM, as compared to its inhibition potency for APP cleavage^[1]. Avagacestat (BMS-708163) (10?μM) combined with gefitinib significantly attenuates the colony growth of PC9/AB2 cells, increases the expression of active caspase 3 and PARP and reduces the expression of Ki-67 in PC9/AB2 cells. Avagacestat (BMS-708163) induces apoptosis and enhances cell cycle arrest at the G1 phase in PC9/AB2 cells. Avagacestat (BMS-708163) treatment effectively downregulates the expression of Notch1, HES1, PI3K and Akt in PC9/AB2 cells^[3].

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

In Vivo

Avagacestat (BMS-708163) significantly reduces both plasma and brain Aβ40 levels relative to control at 10 and 100 mg/kg for the entire dosing interval, demonstrates significant Aβ40 lowering for 8 h after an oral dose of 1 mg/kg, and significantly lowers CSF Aβ40 levels in rats, when measured 5 h after single oral doses ranging from 3 to 100 mg/kg^[1]. Avagacestat (BMS-708163) (10?mg/kg) monotherapy has a minor inhibitory effect on PC9/AB2 tumor growth compared with gefitinib alone. BMS-708163 monotherapy results in a slight increase in caspase 3 expression as well as a mild decrease in Ki-67 expression in vivo. In the xenograft lung cancer samples treated with Avagacestat (BMS-708163) plus gefitinib, there are a marked increase in caspase 3 expression and a reduction in Ki-67 staining^[3].

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. Nr. 1146699-66-2
Appearance Solid
Molecular Weight 520.89
Formel C₂₀H₁₇ClF₄N₄O₄S
Color White to off-white
SMILES

O=S(N([C@@H](C(N)=O)CCC(F)(F)F)CC1=CC=C(C2=NOC=N2)C=C1F)(C3=CC=C(Cl)C=C3)=O
Synonyms

BMS-708163
Versand

Room temperature in continental US; may vary elsewhere.

Speicherung

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

Publications (2)

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Journal Impact Factor

EMBO J

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

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

Lösungsmittel & Löslichkeit

In Vitro:

DMSO : ≥ 100 mg/mL (191.98 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

1.9198 mL

9.5990 mL

19.1979 mL

5 mM

0.3840 mL

1.9198 mL

3.8396 mL

10 mM

0.1920 mL

0.9599 mL

1.9198 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.

Molaritätsrechner

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

Mass Mass

Konzentration Konzentration

Volumen Volumen

Molecular Weight Molecular Weight

Verdünnungsrechner

Konzentration _{(Stammlösung)} × Volumen _{(Stammlösung)} = Konzentration _{(Ziellösung)} × Volumen _{(Ziellösung)}

Konzentration _{(Stammlösung)} Konzentration _{(Stammlösung)}

Volumen _{(Stammlösung)} Volumen _{(Stammlösung)}

Konzentration _{(Ziellösung)} Konzentration _{(Ziellösung)}

Volumen _{(Ziellösung)} Volumen _{(Ziellösung)}

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 90% Corn Oil

Solubility: ≥ 3 mg/mL (5.76 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

Protokoll

Cell Assay^[3]

The cell viability is assessed using a tetrazolium salt (WST-8)-based colorimetric assay from the Cell Counting Kit 8 (CCK-8). The cells are seeded into 96-well plates at an initial density of 5×10³ cells/well and cultured for 24 h, after which the cells are cultured with DMSO, increased concentrations of gefitinib or Avagacestat (BMS-708163) , BIBW2992, or the combination of Avagacestat (BMS-708163) and BIBW2992 for an additional 48 h. The A450 is measured in a microplate reader after 10 µL of CCK-8 solution is added and incubated for 1 h. The percentage of growth is shown relative to untreated controls.

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

Animal Administration^[3]

Four- to six-week-old female Balb/c athymic (nu + /nu +) mice are anesthetized with ether. The mice are acclimatized for one week before being injected with 1.5×10⁶ PC9/AB2 cells that have been resuspended in 200 μL of matrigel. When established tumors of approximately 150-300 mm³ in diameter are detected, the mice are randomly divided into groups and fed orally by gavage with either vehicle (1% methylcellulose, 0.2% Tween 80 in sterilized water), gefitinib (3 mg/kg diluted in vehicle), Avagacestat (BMS-708163) (10 mg/kg diluted in vehicle), or a combination of gefitinib (3 mg/kg) and Avagacestat (BMS-708163) (10 mg/kg) for 5 days/week. Each treatment group consists of eight mice. The tumor volume are measured and calculated every five days using the following formula: π/6×(larger diameter)×(smaller diameter)². After 30 days, mice are killed by cervical dislocation.

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

Reinheit & Dokumentation

Select Batch:

Reinheit: 99.98%

Assay: 99.98%

ee.: 99.98%

Data Sheet (286 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)
- Korean - KR (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)

Verweise

[1]. Gillman KW, et al. Letter Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor. Med Chem Lett, 2010, 1 (3), 120-124. [Content Brief]

[2]. Xie M, et al. γ Secretase inhibitor BMS-708163 reverses resistance to EGFR inhibitor via the PI3K/Akt pathway in lung cancer. J Cell Biochem. 2015 Jun;116(6):1019-27. [Content Brief]

[3]. Crump CJ, et al. BMS-708,163 targets presenilin and lacks notch-sparing activity. Biochemistry. 2012 Sep 18;51(37):7209-11. [Content Brief]

[4]. Borghys H, et al. A canine model to evaluate efficacy and safety of γ-secretase inhibitors and modulators. J Alzheimers Dis. 2012;28(4):809-22. [Content Brief]

[5]. Vladimir Coric, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012 Nov;69(11):1430-40. [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	1.9198 mL	9.5990 mL	19.1979 mL	47.9948 mL
	5 mM	0.3840 mL	1.9198 mL	3.8396 mL	9.5990 mL
	10 mM	0.1920 mL	0.9599 mL	1.9198 mL	4.7995 mL
	15 mM	0.1280 mL	0.6399 mL	1.2799 mL	3.1997 mL
	20 mM	0.0960 mL	0.4799 mL	0.9599 mL	2.3997 mL
	25 mM	0.0768 mL	0.3840 mL	0.7679 mL	1.9198 mL
	30 mM	0.0640 mL	0.3200 mL	0.6399 mL	1.5998 mL
	40 mM	0.0480 mL	0.2400 mL	0.4799 mL	1.1999 mL
	50 mM	0.0384 mL	0.1920 mL	0.3840 mL	0.9599 mL
	60 mM	0.0320 mL	0.1600 mL	0.3200 mL	0.7999 mL
	80 mM	0.0240 mL	0.1200 mL	0.2400 mL	0.5999 mL
	100 mM	0.0192 mL	0.0960 mL	0.1920 mL	0.4799 mL

Keywords

Avagacestat

2 Cited Publications

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Avagacestat

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Publications Citing Use of MedChemExpress (MCE) Avagacestat

Biologische Aktivität

Chemical Information

Publications (2)

Lösungsmittel & Löslichkeit

Protokoll

Reinheit & Dokumentation

Verweise

Help & FAQs

Complete Stock Solution Preparation Table

Avagacestat Related Classifications

HY-50845 Related Classifications