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Gamma Secretase

Avagacestat (1146699-66-2)

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.

Not Intended for Therapeutic Use. For research use only.

CAS: 1146699-66-2 Category

Avagacestat (1146699-66-2) Description:

Avagacestat, also known as BMS-708163, is an oral GSI designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aβ synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class.

Avagacestat (BMS-708163) is a potent γ-secretase inhibitor selective for amyloid precursor protein (APP) over Notch cleavage. Avagacestat inhibits Aβ40 and Aβ42 production with IC50 values of 0.3 nM and 0.27 nM, respectively, compared to IC50 values of 41, 10, 33, and 38 nM respectively for signaling inhibition of the human Notch 1-4 proteins. At higher concentrations BMS-708163 has been found to reverse sensitivity to the EGFR tyrosine kinase inhibitor gefitinib, thought to be by Notch inhibition.

Avagacestat (1146699-66-2) Specifications:

Product Name Avagacestat
Synonyms Avagacestat; BMS708163; BMS-708163; BMS 708163.
Chemical Names (R)-2-(4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide
Purity >98% (or refer to the Certificate of Analysis)
CAS Number 1146699-66-2
Molecular Formula C20H17ClF4N4O4S
Molecular Weight 520.88
Monoisotopic Mass 520.06 g/mol
MDL number MFCD13195458
InChIKey MKQKPLQMNCXTJE-VEZQGTPESA-L
InChi Code InChI=1S/C22H25N6O8P.2Na/c1-2-23-22(29)27-19-16-20(25-11-24-19)28(12-26-16)21-18-17(14(34-21)10-33-37(30,31)32)35-15(36-18)9-8-13-6-4-3-5-7-13;;/h3-9,11-12,14-15,17-18,21H,2,10H2,1H3,(H2,30,31,32)(H2,23,24,25,27,29);;/q;2*+1/p-2/b9-8+;;/t14-,15+,17-,18-,21-;;/m1../s1
SMILES O=C(N)[[email protected]](N(CC1=CC=C(C2=NOC=N2)C=C1F)S(=O)(C3=CC=C(Cl)C=C3)=O)CCC(F)(F)F
Form Powder
Color white to beige
Solubility  Soluble in DMSO, not in water
Storage Temp.  Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Shelf life >5 years if stored properly
Handling Protect from air and light
Application A potent, orally bioavailable inhibitor of γ-secretase

 


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RIDADR NONH for all modes of transport

References:

  • 1: Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens R. A contrast in safety, pharmacokinetics, and pharmacodynamics across age groups after a single 50-mg oral dose of the γ-secretase inhibitor avagacestat. Br J Clin Pharmacol. 2012 May 23. doi: 10.1111/j.1365-2125.2012.04339.x. [Epub ahead of print] PubMed PMID: 22616739.
  • 2: Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012 Mar;34(3):654-67. Epub 2012 Feb 28. PubMed PMID: 22381714.
  • 3: Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H, Shitaka Y, Ni K, Matsuoka N. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci. 2012 Feb 8;32(6):2037-50. PubMed PMID: 22323718.
  • 4: Hartley RF, Huang Y, Cassidy M, Razler TM, Qian F, Hussain MA. Degradation kinetics and mechanism of an oxadiazole derivative, design of a stable drug product for BMS-708163, a γ-secretase inhibitor drug candidate. J Pharm Sci. 2012 Sep;101(9):3124-33. doi: 10.1002/jps.23050. Epub 2012 Jan 19. PubMed PMID: 22262489.
  • 5: Lu Y, Zhang L, Nolan CE, Becker SL, Atchison K, Robshaw AE, Pustilnik LR, Osgood SM, Miller EH, Stepan AF, Subramanyam C, Efremov I, Hallgren AJ, Riddell D. Quantitative pharmacokinetic/pharmacodynamic analyses suggest that the 129/SVE mouse is a suitable preclinical pharmacology model for identifying small-molecule γ-secretase inhibitors. J Pharmacol Exp Ther. 2011 Dec;339(3):922-34. Epub 2011 Sep 19. PubMed PMID: 21930801.

1 review for Avagacestat (1146699-66-2)

  1. Rated 5 out of 5

    Cofttek

    Never had such good experience before,The Avagacestat (1146699-66-2) is high purity,also customer service is pretty nice !gotta try!!

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