A potent inhibitor of γ-secretase
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Avagacestat

Item No. 16711

Product Insert (PDF)Safety Data Sheet (SDS) (PDF)
Technical Information
Formal Name
(2R)-2-[[(4-chlorophenyl)sulfonyl][[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoro-pentanamide
CAS Number
1146699-66-2
Synonyms
  • BMS 708163
Molecular Formula
C20H17ClF4N4O4S
Formula Weight
520.9
Purity
≥98%
Formulation (Request formulation change)
A crystalline solid
Solubility(Learn about Variance in Solubility)
DMF: 2 mg/mlDMSO: 15 mg/mlDMSO:PBS(pH 7.2) (1:2): 0.3 mg/mlEthanol: 5 mg/ml
λmax
244 nm
SMILES
O=S(N([C@@H](C(N)=O)CCC(F)(F)F)CC1=CC=C(C2=NOC=N2)C=C1F)(C3=CC=C(Cl)C=C3)=O
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
InChi Key
XEAOPVUAMONVLA-QGZVFWFLSA-N
Shipping & Storage Information
Storage
-20°C
Shipping
Room temperature in continental US; may vary elsewhere
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    1 mg

    $49

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    5 mg

    $213

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    10 mg

    $376

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    Product Description

    γ-Secretase is a protease complex that cleaves single-pass transmembrane proteins, such as Notch receptors and β-amyloid precursor protein (APP), within the transmembrane domain.1,2 Avagacestat is a potent, orally bioavailable inhibitor of γ-secretase that more potently inhibits the cleavage of APP to Aβ40 than signaling through Notch (IC50s = 0.30 and 58 nM, respectively).3 It shows good pharmacokinetics in rats, dogs, and humans and passes the blood-brain barrier, reducing plasma, brain, and cerebrospinal fluid Aβ40 levels.3,4 While suppressing the production of Aβ38, Aβ40, and Aβ42, γ-secretase inhibitors, including avagacestat, increase the level of APP β-C-terminal fragment, both in vitro and in vivo, altering cell function.5 Avagacestat may impact Notch signaling in vivo, although it is generally considered a “Notch-sparing” γ-secretase inhibitor.6

    WARNING This product is not for human or veterinary use.

    References & Product Citations
    Product Description References

    1. Andersson, E.R., and Lendahl, U. Therapeutic modulation of Notch signalling - are we there yet? Nat. Rev. Drug Discov. 13(5), 357-378 (2014).

    2. Jurisch-Yaksi, N., Sannerud, R., and Annaert, W. A fast growing spectrum of biological functions of γ-secretase in development and disease. Biochim. Biophys. Acta 1828(12), 2815-2827 (2013).

    3. Gillman, K.W., Starrett, J.E., Jr., Parker, M.F., et al. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med. Chem. Lett. 1(3), 120-124 (2010).

    4. Albright, C.F., Dockens, R.C., Meredith, J.E., Jr., et al. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J. Pharmacol. Exp. Ther. 344(3), 686-695 (2013).

    5. Mitani, Y., Yarimizu, J., Saita, K., et al. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J. Neurosci. 32(6), 2037-2050 (2012).

    6. Crump, C.J., Castro, S.V., Wang, F., et al. BMS-708,163 targets presenilin and lacks notch-sparing activity. Biochemistry 51(37), 7209-7211 (2012).