BMS-708163 - CAS 1146699-66-2
Catalog number: 1146699-66-2
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C20H17ClF4N4O4S
Molecular Weight:
520.89
COA:
Inquire
Targets:
γ-secretase
Description:
BMS-708163, also called Avagacestat, is a potent, orally bioavailable inhibitor of γ-secretase that more potently inhibits the cleavage of APP (IC50s = 0.30 nM) to Aβ40 than signaling through Notch (IC50s = 58 nM).
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Brife Description:
A potent, orally bioavailable inhibitor of γ-secretase
Appearance:
Solid powder
Synonyms:
(2R)-2-[(4-chlorophenyl)sulfonyl-[[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide; Avagacestat; BMS-708163; 1146699-66-2; BMS 708163; UNII-TQ44WWY45Q; BMS-708163-01; Avagacestat (USAN); Avagacestat [USAN]; (2R)-2-[N-[(4-CHLOROPHENYL)SULFONYL]-N-[2-FLUORO-4-(1,2,4-OXADIAZOL-3-YL)BENZYL]AMINO]-5,5,5-TRIFLUOROPENTANAMIDE; (R)-2-(4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide; BMS708163, 1146699-66-2; (2R)-5,5,5-trifluoro-2-(N-{[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl}4-chlorobenzenesulfonamido)pentanamide; 123886-EP2295417A1; (2R)-2-(N-((4-Chlorophenyl)sulfonyl)-N-((2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl)methyl)amino)-5,5,5-trifluoropentanamide; (2R)-2-[[(4-chlorophenyl)-sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide; (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoro-pentanamide; (2R)-2-[[(4-Chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide
Solubility:
Soluble to 100 mg/mL in DMSO and 7.5 mg/mL in Ethanol
Storage:
Store in a cool and dry place and at 0 - 4℃ for short term (days to weeks) or -34℃ for long term (months to years).
MSDS:
Inquire
Boiling Point:
652.258℃ at 760 mmHg
Density:
1.488 g/cm3
InChIKey:
XEAOPVUAMONVLA-QGZVFWFLSA-N
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
Canonical 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
1.Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men.
Tong G1, Castaneda L, Wang JS, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright C, Dockens RC. Clin Drug Investig. 2012 Nov;32(11):761-9. doi: 10.1007/s40261-012-0006-4.
BACKGROUND: The concentration of amyloid β (Aβ) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-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 Aβ concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability.
2.A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects.
Dockens R1, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Tong G. Clin Pharmacokinet. 2012 Oct 1;51(10):681-93.
BACKGROUND AND OBJECTIVES: Avagacestat is an orally active γ-secretase inhibitor that selectively inhibits amyloid β (Aβ) 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.
3.Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.
Coric V1, Salloway S2, van Dyck CH3, Dubois B4, Andreasen N5, Brody M6, Curtis C7, Soininen H8, Thein S9, Shiovitz T10, Pilcher G1, Ferris S11, Colby S1, Kerselaers W1, Dockens R1, Soares H1, Kaplita S1, Luo F1, Pachai C12, Bracoud L12, Mintun M13, Grill JAMA Neurol. 2015 Nov;72(11):1324-33. doi: 10.1001/jamaneurol.2015.0607.
IMPORTANCE: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.
4.γ Secretase inhibitor BMS-708163 reverses resistance to EGFR inhibitor via the PI3K/Akt pathway in lung cancer.
Xie M1, He J, He C, Wei S. J Cell Biochem. 2015 Jun;116(6):1019-27. doi: 10.1002/jcb.25056.
Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitor (TKI). Acquired resistance to EGFR TKI develops after prolonged treatment. The aim of this study was to investigate the effect of the novel γ secretase inhibitor BMS-708163 on acquired resistance to the EGFR TKI gefitinib. We did not observe known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation and MET gene amplification in the gefitinib-resistant PC9/AB2 cells. BMS-708163 inhibited PI3K/Akt expression and sensitized PC9/AB2 cells to gefitinib-induced cytotoxicity. In contrast, BMS-708163 had no significant effect on gefitinib sensitivity in PC9 parental cells. Combined treatment with BMS-708163 and gefitinib induced high levels of apoptosis. Our in vivo studies showed that combined treatment of gefitinib and BMS-708163 inhibited the growth of PC9/AB2 xenografts. In conclusion, our data show that combined treatment of gefitinib and γ secretase inhibitors may be useful for treating lung adenocarcinomas harboring EGFR mutations with acquired gefitinib resistance.
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