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BMS-708163 (Avagacestat)

γ-secretase inhibitor CAS# 1146699-66-2

BMS-708163 (Avagacestat)

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Quality Control of BMS-708163 (Avagacestat)

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Chemical structure

BMS-708163 (Avagacestat)

3D structure

Chemical Properties of BMS-708163 (Avagacestat)

Cas No. 1146699-66-2 SDF Download SDF
PubChem ID 46883536 Appearance Powder
Formula C20H17ClF4N4O4S M.Wt 520.88
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Avagacestat
Solubility DMSO : ≥ 100 mg/mL (191.98 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name (2R)-2-[(4-chlorophenyl)sulfonyl-[[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide
SMILES C1=CC(=CC=C1S(=O)(=O)N(CC2=C(C=C(C=C2)C3=NOC=N3)F)C(CCC(F)(F)F)C(=O)N)Cl
Standard InChIKey XEAOPVUAMONVLA-QGZVFWFLSA-N
Standard InChI InChI=1S/C20H17ClF4N4O4S/c21-14-3-5-15(6-4-14)34(31,32)29(17(18(26)30)7-8-20(23,24)25)10-13-2-1-12(9-16(13)22)19-27-11-33-28-19/h1-6,9,11,17H,7-8,10H2,(H2,26,30)/t17-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of BMS-708163 (Avagacestat)

DescriptionBMS-708163 is a potent, selective, orally bioavailable inhibitor of γ-secretase with IC50 value of 0.3 nM and 0.27 nM for Aβ40 and Aβ42, respectively.
Targetsγ-secretaseγ-secretase    
IC500.3 nM (Aβ40)0.27 nM (Aβ42)    

Protocol

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 BMS708163, BIBW2992, or the combination of BMS708163 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.

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), BMS-708163 (10 mg/kg diluted in vehicle), or a combination of gefitinib (3 mg/kg) and 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.

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

BMS-708163 (Avagacestat) Dilution Calculator

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BMS-708163 (Avagacestat) Molarity Calculator

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Preparing Stock Solutions of BMS-708163 (Avagacestat)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9198 mL 9.5991 mL 19.1983 mL 38.3966 mL 47.9957 mL
5 mM 0.384 mL 1.9198 mL 3.8397 mL 7.6793 mL 9.5991 mL
10 mM 0.192 mL 0.9599 mL 1.9198 mL 3.8397 mL 4.7996 mL
50 mM 0.0384 mL 0.192 mL 0.384 mL 0.7679 mL 0.9599 mL
100 mM 0.0192 mL 0.096 mL 0.192 mL 0.384 mL 0.48 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on BMS-708163 (Avagacestat)

BMS-708163 is a potent selective and orally bioavailable inhibitor of γ-secretase with IC50 value of 0.3nM [1].

The cleavage of amyloid precusor protein APP by γ-secretase causes the production of Aβ40 and Aβ42, which are cytotoxic and cause AD. In vitro assay shows BMS-708163 inhibits the formation of Aβ40 and Aβ42 in H4-8Sw cells. It also inhibits the human recombinant CYPs in vitro with IC50 value of 20μM. Notch receptor is another substrate of γ-secretase. The inhibition of Notch signal pathway results in some side effects. It is shown that the activity of BMS-708163 to inhibit Notch is 190-fold weaker than to APP. In female rats, oral administration of BMS-708163 significantly reduces the production of Aβ in plasma and brain at 10mg/kg and 100mg/kg. In addition, BMS-708163 also reduces Aβ in brain and CSF in male beagle dogs [1].

References:
[1] Gillman KW, Starrett JE Jr, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, Williams R, Meredith JE Jr, Burton CR, Barten DM, Toyn JH, Roberts SB, Lentz KA, Houston JG, Zaczek R, Albright CF, Decicco CP, Macor JE, Olson RE. Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor. ACS Med Chem Lett. 2010 Mar 22;1(3):120-4.

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References on BMS-708163 (Avagacestat)

A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects.[Pubmed:23018531]

Clin Pharmacokinet. 2012 Oct 1;51(10):681-93.

BACKGROUND AND OBJECTIVES: Avagacestat is an orally active gamma-secretase inhibitor that selectively inhibits amyloid beta (Abeta) synthesis in cell culture and animal models. The objective of the current study was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of avagacestat over 28 days in healthy young men and elderly men and women in a placebo-controlled, sequential-panel, ascending multiple-dose study. METHODS: Thirty-three young men were assigned to four serial dose groups of avagacestat 15, 50, 100 or 150 mg (n = 6-7 per dose), or placebo (n = 2 per dose panel; 8 subjects total) once daily for 28 days. Elderly men and women were assigned to serial dose groups of avagacestat 50 mg and then 100 mg (n = 7 men, 6 women) or placebo (n = 2 men, 2 women) once daily for 14 days per dose level. RESULTS: Avagacestat was rapidly absorbed, had a terminal elimination half-life of 38-65 h, and reached a steady-state concentration by day 10 of daily dosing. Exposure in young subjects increased in proportion to dose. There were no apparent differences in steady-state area under the plasma concentration-time curve between young and elderly subjects; however, elderly subjects demonstrated a higher maximum plasma concentration for avagacestat. Doses of avagacestat >50 mg/day reduced steady-state trough concentrations of CSF Abeta(1-38), Abeta(1-40) and Abeta(1-42) in a dose-dependent fashion over 28 days of daily dosing. There were no signs of potential Notch-related dose-limiting toxicities. CONCLUSION: The results support continued evaluation of avagacestat in an elderly target population with predementia and mild to moderate Alzheimer's disease.

Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Abeta levels in healthy young men.[Pubmed:23018285]

Clin Drug Investig. 2012 Nov;32(11):761-9.

BACKGROUND: The concentration of amyloid beta (Abeta) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of gamma-secretase inhibition. Avagacestat is a selective gamma-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Abeta concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability. METHODS: This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses. RESULTS: 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Abeta(1-38), Abeta(1-40) and Abeta(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups. CONCLUSION: Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Abeta concentrations, suggestive of gamma-secretase inhibition. The results warrant further clinical study in patients with AD.

Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral gamma-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers.[Pubmed:22381714]

Clin Ther. 2012 Mar;34(3):654-67.

BACKGROUND: gamma-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-beta (Abeta) accumulation. BMS-708163 (Avagacestat) is an oral GSI designed for selective inhibition of Abeta synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Abeta synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Abeta synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds. Presented here are the results of the first in-human study for this new GSI compound. OBJECTIVE: The goal of this study was to assess the tolerability profile, pharmacokinetic properties, and effects on pharmacodynamic markers (Abeta, trefoil factor family 3 protein, dual specificity phosphatase 6, and hairy and enhancer of split-1) of single, oral doses of avagacestat in healthy, young, male volunteers. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study in 8 healthy young men (age, 18-45 years) per dosing panel. Each study participant was randomized to receive a single dose of placebo (n = 2) or avagacestat (n = 6 for each dose) as an oral solution in 1 of 9 sequential dose panels (0.3, 1.5, 5, 15, 50, 100, 200, 400, and 800 mg). For determination of avagacestat, blood samples were obtained before dosing and for up to 144 hours after dosing. For participants in the 800-mg avagacestat dose panel, additional samples were obtained at 216, 312, and 648 hours. For 40-amino acid isoform of Abeta (Abeta(1-40)) assessment, plasma samples were collected before avagacestat administration and up to 72 hours after dosing. RESULTS: Avagacestat concentrations peaked quickly after oral administration and then had a biphasic decrease in concentrations with a prolonged terminal phase. Exposures were proportional with doses up to 200 mg. Avagacestat was well tolerated at single oral doses up to 800 mg, with a biphasic effect on plasma Abeta(1-40). Adverse events were predominately mild to moderate in severity with no evidence of dose dependence up to 200 mg. CONCLUSIONS: Results from this single-ascending dose study suggest that avagacestat was tolerated at a single-dose range of 0.3 to 800 mg and suitable for further clinical development.

Description

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.

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