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Purity: =100%
Avagacestat (formerly known as BMS708163) is a potent, selective, orally bioactive γ-secretase inhibitor of Aβ40 and Aβ42 that may have anti-AD (Alzheimer's disease) properties. With IC50 values of 0.3 nM and 0.27 nM, respectively, it suppresses Aβ40 and Aβ42 and exhibits 193-fold selectivity against Notch. Currently under development as a treatment for mild to moderate AD and predementia, avagacestat is intended to selectively inhibit Aβ synthesis. It is possible that Avagacestat will result in fewer toxic adverse events than other less selective compounds because it produced up to 190-fold greater selectivity for Aβ synthesis than Notch processing in preclinical studies.
| Targets |
γ-secretase (IC50 = 0.27 nM); γ-secretase (IC50 = 0.30 nM); CYP2C19 (IC50 = 20 μM); NICD (IC50 = 0.84 nM)
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| ln Vitro |
Avagacestat (BMS-708163) has a lower potency (IC50=58±23 nM) for inhibiting Notch processing than it does for inhibiting APP cleavage[1]. When combined with gefitinib, avagacestat (BMS-708163) (10µM) significantly inhibits PC9/AB2 cell colony growth, increases the expression of PARP and active caspase 3, and decreases PC9/AB2 cell Ki-67 expression. In PC9/AB2 cells, avagacestat (BMS-708163) increases cell cycle arrest at the G1 phase and causes apoptosis. Treatment with Avagacestat (BMS-708163) efficiently suppresses Notch1, HES1, PI3K, and Akt expression in PC9/AB2 cells[3].
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| ln Vivo |
Avagacestat (BMS-708163) exhibits a significant lowering of Aβ40 for 8 hours following an oral dose of 1 mg/kg, significantly lowers CSF Aβ40 levels in rats when measured 5 hours after single oral doses ranging from 3 to 100 mg/kg, and significantly lowers both plasma and brain Aβ40 levels relative to control at 10 and 100 mg/kg for the entire dosing interval[1]. When compared to gefitinib alone, Avagacestat (BMS-708163) (10 mg/kg) monotherapy has a negligible inhibitory effect on PC9/AB2 tumor growth. In vivo, BMS-708163 monotherapy causes a slight decrease in Ki-67 expression and a slight increase in caspase 3 expression. Avagacestat (BMS-708163) plus gefitinib treatment resulted in a significant decrease in Ki-67 staining and an increase in caspase 3 expression in the xenograft lung cancer samples[3].
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| Cell Assay |
An assay from the Cell Counting Kit 8 (CCK-8) that uses tetrazolium salts (WST-8) as its basis is used to measure the viability of the cells. Initially, the cells are seeded into 96-well plates at a density of 5×103 cells/well and cultured for 24 hours. Following this, the cells are cultured for an additional 48 hours with DMSO, higher concentrations of gefitinib or Avagacestat (BMS-708163), BIBW2992, or the combination of Avagacestat (BMS-708163) and BIBW2992. Once 10 µL of CCK-8 solution has been added and incubated for one hour, the A450 is measured in a microplate reader. The growth percentage is displayed in relation to the untreated control group.
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| Animal Protocol |
Female Balb/c athymic (nu + /nu +) mice aged four to six weeks are put to sleep with ether. Following a week of acclimation, 1.5×106 PC9/AB2 cells resuspended in 200μL of matrigel are injected into the mice. Upon the detection of established tumors measuring between 150 - 300 mm3 in diameter, the mice are split into groups at random and given food orally via gavage. The food options include vehicle (1% methylcellulose and 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 five days per week. The number of mice in each treatment group is 8. Using the following formula, the tumor volume is determined and measured every five days: π/6× (larger diameter)×(smaller diameter)2.
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| References |
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| Additional Infomation |
Avagacestat is an oxadiazole and a ring assembly.
Avagacestat has been investigated for the basic science and treatment of Alzheimer Disease. |
| Molecular Formula |
C20H17CLF4N4O4S
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| Molecular Weight |
520.88
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| Exact Mass |
520.059
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| Elemental Analysis |
C, 46.12; H, 3.29; Cl, 6.81; F, 14.59; N, 10.76; O, 12.29; S, 6.16
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| CAS # |
1146699-66-2
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| Related CAS # |
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| PubChem CID |
46883536
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
652.3±65.0 °C at 760 mmHg
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| Flash Point |
348.3±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.564
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| LogP |
4.89
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
34
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| Complexity |
792
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1[H])S(N(C([H])([H])C1C([H])=C([H])C(C2=NOC([H])=N2)=C([H])C=1F)[C@@]([H])(C(N([H])[H])=O)C([H])([H])C([H])([H])C(F)(F)F)(=O)=O
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| InChi Key |
XEAOPVUAMONVLA-QGZVFWFLSA-N
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| InChi Code |
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
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| Chemical Name |
(2R)-2-[(4-chlorophenyl)sulfonyl-[[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide
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| Synonyms |
BMS-708163; BMS708163; Avagacestat; BMS 708163
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (5.76 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9198 mL | 9.5991 mL | 19.1983 mL | |
| 5 mM | 0.3840 mL | 1.9198 mL | 3.8397 mL | |
| 10 mM | 0.1920 mL | 0.9599 mL | 1.9198 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00901498 | Completed | Drug: BMS-708163 | Alzheimer's Disease Healthy |
Bristol-Myers Squibb | May 2009 | Phase 1 |
| NCT00979316 | Completed | Drug: BMS-708163 Drug: Placebo |
Alzheimer Disease | Bristol-Myers Squibb | September 2009 | Phase 1 |
| NCT00810147 | Completed | Drug: BMS-708163 Drug: Placebo |
Alzheimer's Disease | Bristol-Myers Squibb | February 2009 | Phase 2 |
| NCT01002079 | Completed | Drug: BMS-708163 Drug: Rifampin |
Alzheimer Disease | Bristol-Myers Squibb | August 2010 | Phase 1 |
| NCT01079819 | Completed | Drug: BMS-708163 Drug: Placebo |
Alzheimer's Disease | Bristol-Myers Squibb | April 2010 | Phase 1 |
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