Avagacestat (BMS-708163)

Catalog No.S1262

Avagacestat (BMS-708163) is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, demonstrating a 193-fold selectivity against Notch. Phase 2.

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Avagacestat (BMS-708163) Chemical Structure

Avagacestat (BMS-708163) Chemical Structure
Molecular Weight: 520.88

Validation & Quality Control

3 customer reviews :

Quality Control & MSDS

Related Compound Libraries

Avagacestat (BMS-708163) is available in the following compound libraries:

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  • Gamma-secretase Inhibitor in Clinical Trial

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Product Information

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Product Description

Biological Activity

Description Avagacestat (BMS-708163) is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, demonstrating a 193-fold selectivity against Notch. Phase 2.
Targets γ secretase(Aβ42) [1] γ secretase(Aβ40) [1]
IC50 0.27 nM 0.3 nM
In vitro BMS-708163 exhibits weaker selectivity for inhibition of Notch processing with 193-fold IC50 value. [1]
In vivo Oral administration of BMS-708163 significantly reduces Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. BMS-708163 has no dose-limiting effects in dogs (3 mg/kg during 6 months), with a high brain to plasma ratio (2.4). [1]
Features Appears to be more “notch sparing” than semagacestat (LY450139).

Protocol(Only for Reference)

Kinase Assay: [1]

Inhibition of Aβ formation BMS-708163 is assayed for Aβ40 or Aβ42 inhibition in cells using H4 APP751 SWE clone 8.20, an H4 neuroglioma cell line stably expressing the Swedish mutant of APP751. Cells are maintained in log phase through twice weekly passage at a 1:20 dilution. For IC50 determinations, 30 μL cells (1.5×104 cells/well) in DMEM media containing 0.0125% BSA are seeded directly into 384-well plates containing 0.1 μL serially diluted BMS-708163 in DMSO. Following incubation for 19 hours in 5% CO2 at 37 °C, plates are briefly centrifuged (103 rpm, 5 min). A 10 μL aliquot from each well is transferred to a second assay plate for Aβ40 measurements. Antibody cocktails are freshly prepared by dilution into 40 mM Tris-HCl (pH 7.4) with 0.2% BSA and added to assay plates. For Aβ42 measurements, antibodies specific for the Aβ42 neoepitope (565, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and the N-terminal sequence of Aβ peptide (26D6, developed at SIBIA/Bristol-Myers Squibb; conjugated to APC) are mixed and 20 μL of the mixture is added to each well of the incubated cell plate yielding a final concentration of 0.8 ng/well 565 and 75 ng/well 26D6. For the Aβ40 measurements, antibodies specific for the Aβ40 neoepitope (TSD, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and 26D6 as described above are mixed and 20 μL of the mixture is added to the 10 μL aliquots which have been removed previously from the cell plate yielding a final concentration of 1.6 ng/well TSD and 17.5 ng/well 26D6. Assay plates containing antibodies are sealed with aluminum foil and incubated overnight at 4 °C. Signal is determined using a Viewlux counter and IC50 values are determined.

Animal Study: [1]

Animal Models Female Harlan Sprague-Dawley rats or ATM-405-142K9 with 7- 10 month old Na?ve, grade II beagles
Formulation 99% PEG-400, 1% Tween-80 (rats) or 94% labrafil-1944, 5% ethanol, 1% tween-80 (dogs)
Dosages 10 mg/kg (rats) or 2.5 mg/kg (dogs)
Administration Dosed daily by oral gavage

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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] Gillman KW, et al. Med Chem Lett, 2010, 1 (3), 120–124.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01002079 Completed Alzheimer Disease Bristol-Myers Squibb|PRA Health Sciences August 2010 Phase 1
NCT01079819 Completed Alzheimers Disease Bristol-Myers Squibb April 2010 Phase 1
NCT01057030 Completed Alzheimer Disease Bristol-Myers Squibb March 2010 Phase 1
NCT01039194 Completed Alzheimer Disease Bristol-Myers Squibb January 2010 Phase 1
NCT01042314 Completed Alzheimer Disease Bristol-Myers Squibb January 2010 Phase 1

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Chemical Information

Download Avagacestat (BMS-708163) SDF
Molecular Weight (MW) 520.88
Formula

C20H17ClF4N4O4S

CAS No. 1146699-66-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 104 mg/mL (199.66 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
* <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 (2R)-2-(N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide

Customer Product Validation(3)


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Rating
Source Stem Cells 2014 32(1), 301-12. Avagacestat (BMS-708163) purchased from Selleck
Method CellTiter-Blue assay
Cell Lines GICs
Concentrations 0.1-10 uM
Incubation Time 72 h
Results γ Secretase inhibitor BMS-708163 effectively showed dose-dependent growth inhibition of GICs. panel of GICS lines was treated with various concentrations of γ secretase inhibitor BMS-708163. Cells were treated with increasing concentrations of γ secretase inhibitor in triplicate wells for 72 hours, and cell viability was assessed by CellTiter-Blue assay as described in Materials and Methods. The results shown are of a single experiment with 3 independent replicates cell viability was measured by CellTiter-Blue assay. The graph depicts cell viability at 72 hours. Cell viability in the vehicle control was considered as to be 100%.

Click to enlarge
Rating
Source Stem Cells 2014 32(1), 301-12. Avagacestat (BMS-708163) purchased from Selleck
Method Western blot
Cell Lines GICs
Concentrations 0-5 uM
Incubation Time 0-72 h
Results γ Secretase inhibitor BMS-708163 suppresses Notch signaling pathway in a dose- or time-dependent manner.

Click to enlarge
Rating
Source J Biol Chem 2014 289(30), 20871-8. Avagacestat (BMS-708163) purchased from Selleck
Method Immunofluorescence
Cell Lines Tg2576 MEFs
Concentrations 10 uM
Incubation Time 48 h
Results Treatment with 10 nm BMS-708163 partly suppressed nuclear import (C and D). When Tg2576 MEFs were incubated with the β-secretase inhibitor followed by ascorbate, nuclear anMan-staining was undetectable.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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