Semagacestat (LY450139)

製品コードS1594

Semagacestat (LY450139)化学構造

分子量(MW):361.44

Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM in H4 human glioma cell. Phase 3.

サイズ 価格(税別)  
JPY 31540.00
JPY 28220.00
JPY 53120.00
JPY 161020.00

カスタマーフィードバック(3)

  • Cultures were assessed in A for TRAP by enzyme histochemistry 5-8 days following exposure to Rankl. Values are means ± S.D.; n = 6 for all data sets except for Notch2Q2319X DMSO at day 5 where n = 5; the right upper panel shows representative culture fields of TRAP-stained multinucleated cells 8 days after the addition of Rankl.

    J Biol Chem, 2016, 291(4):1538-51.. Semagacestat (LY450139) purchased from Selleck.

    None of the AZ GSMs (square, triangle, and ×) or E2012 (O) affect Notch processing, whereas the GSIs L685458, DBZ, MRK-560, and Semagacestat do, as measured by quantifying the amount of nuclearly trans- located NICD in HEK293 cells stably transfected with △ENotch using immunocytochemistry. % NICD translocation is set relative to 0.5% DMSO (100%) and 0.5 μM L685458(0%)controls(mean±S.E., n=2).

    J Biol Chem 2012 287(15), 11810-9. Semagacestat (LY450139) purchased from Selleck.

  • HEK/APPswe cells were either left non-treated (-) or exposed to the γ-secretase inhibitor (GSI) semagacestat (+) for 19 h prior to cell harvesting and membrane preparation (Substrate accumulation). Exposure of cells with GSI prior to membrane preparation results in higher Aβ1-42 and Aβx-42 signals as compared to membranes derived from non-GSI treated cells. Direct addition of semagacestat to the membranes in the novo Aβ production assay inhibited Aβ production (Semagacestat (1 µM)). The amount of Aβx-42 is higher than Aβ1-42 suggesting that C83 is the major substrate for the Aβ42 signal detected.

    J Biol Chem 2014 289(3), 1540-50. Semagacestat (LY450139) purchased from Selleck.

製品安全説明書

Gamma-secretase阻害剤の選択性比較

生物活性

製品説明 Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM in H4 human glioma cell. Phase 3.
特性 The best characterized γ-secretase inhibitor that has reached the clinic.
ターゲット
γ secretase(Aβ42) [1]
(H4 human glioma cells)
γ secretase(Aβ38) [1]
(H4 human glioma cells)
γ secretase(Aβ40) [1]
(H4 human glioma cells)
Notch [1]
(H4 human glioma cells)
10.9 nM 12.0 nM 12.1 nM 14.1 nM
体外試験

Semagacestat reduces the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium, with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively, without affecting cell viability. Semagacestat also increases β-CTF in cell lysates with ECmax of 16.0 nM, and the increase can be unexpectedly attenuated at high concentrations. Semagacestat inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/Aβ42 IC50 only 1.3. [1] Semagacestat causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 of 111 nM from murine CTX expressing endogenous murine APP, but murine Aβ42 formation in CTX is roughly 12-fold less than Aβ40 in accordance with data for neurons from wild type mice. [2]

細胞データ
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
CHO cells MVzGeY5kfGmxbjDhd5NigQ>? MXTJcohq[mm2aX;uJI9nKGejbX3hMZNm[3KndHHz[UBqdiCFSF:gZ4VtdHNiYYPz[ZN{\WRiZYjwdoV{e2mwZzDBVHBUfyCjc4Pld5Nm\CCjczDpcohq[mm2aX;uJI9nKGGveXzvbYQh[mW2YTixJJRwKHhrIIPlZ5JmfGmxbjDh[pRmeiCxdnXycolocHRiaX7jeYJifGmxbjDifUBGVEmVQTygSWQ2OD1yLkCxOUDPxE1? NX\3N4RjOjN5MUO2OVY>
human SH-SY5Y cells MojtSpVv[3Srb36gZZN{[Xl? M4C1dGlvcGmkaYTpc44hd2ZiZ3HtcYEhe2WlcnX0ZZNmNW2nZHnheIVlKGGveXzvbYQh[mW2YTCoNUB1dyB2MDmgdJJw\HWldHnvckBqdiCqdX3hckBUUC2VWUXZJINmdGy|LDDJR|UxRTBwMEO4JO69VQ>? M4P5UlE6Pjl2NE[3
African green monkey CV1 cells NW\KbIFUTnWwY4Tpc44h[XO|YYm= NXLQWoNHUW6qaXLpeIlwdiCxZjDnZY1u[S2|ZXPy[ZRie2ViZYjwdoV{e2WmIHnuJIFnemmlYX6g[5Jm\W5ibX;ub4V6KEOYMTDj[YxteyClb3X4dJJme3OrbnegS4FtPCCGTlGtZolv\GmwZz;0doFve2GldHn2ZZRqd25iZH;tZYlvKGG|c3Xzd4VlKGG|IHnubIljcXSrb36gc4Yhdm:2Y3igdJJw[2W|c3nu[{BjgSCudXPp[oVz[XOnIILldI9zfGW{IHHzd4F6NCCLQ{WwQVAvOzF4MkOg{txO M1jpS|IxODV4NUSx

他の多くの細胞株試験データをご覧になる場合はこちらをクリックして下さい

体内試験 Oral administration of Semagacestat (1 mg/kg) to 5.5-month old APP-transgenic Tg2576 mice significantly ameliorates memory deficits on spatial working memory using the Y-maze task, which disappears after 8 days subchronic dosing. LY450139 decreases hippocampal levels of both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction) and increases β-CTF at 0.3-10 mg/kg in a dose dependent manner with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin or EphA4, in the brain, but impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice failing to restore cognitive deficits in the Y-maze test. [1]

お薦めの試験操作(参考用のみ)

キナーゼ試験:[1]
+ 展開

Cellular APP processing assay and Notch signaling assay:

H4 human glioma cells stably overexpressing human wild-type APP695 are treated with Semagacestat at various concentrations for 24 hours. Levels of Aβ42, Aβ40, and Aβ38 in the media are measured using separate ELISA kits. The expression vector of the constitutively active form of Notch (NotchΔE), encoding bases 1-60 and 5193-6657 of the human Notch1 coding region (NM_017617), is constructed into a pcDNA3.1 vector with a sequence modification from mouse to human. Notch signaling activity is evaluated using Cignal RBP-Jk Reporter Assay kit. RBP-Jk protein [CSL/CBF1/Su(H)/Lag1] is a transcription factor activated with Notch intracellular domain produced by γ-secretase. H4 cells are transiently transfected with the human NotchΔE expression vector and the RBP-Jk-responsive luciferase construct using Lipofectamine 2000, and then exposed to various concentrations of Semagacestat for 16 hours. Notch signaling is measured based on luciferase activity in the cell lysate using the Dual-Glo Luciferase Assay System.
細胞試験: [2]
+ 展開
  • 細胞株: Murine cortical neurons and cerebellar granule cells
  • 濃度: Dissolved in DMSO, final concentration ~10 μM
  • 反応時間: 24 hours
  • 実験の流れ: Cells are incubated with Semagacestat for 24 hours. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) following incubation with 0.5 mg/mL MTT for 60 minutes. For the detection of sAPP species, cells are lysed and analysed by western blotting.
    (参考用のみ)
動物試験:[1]
+ 展開
  • 動物モデル: Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L)
  • 製剤: Dissolved in 0.5% methyl cellulose.
  • 投薬量: ~30 mg/kg
  • 投与方法: Orally administered once daily
    (参考用のみ)

溶解度 (25°C)

体外 DMSO 72 mg/mL (199.2 mM)
Ethanol 41 mg/mL (113.43 mM)
Water Insoluble
体内 左から(NMPから)右の順に溶剤を製品に加えます(文献ではなく、Selleckの実験によるデータ):
0.5% methylcellulose
混合させたのち直ちに使用することを推奨します。
30 mg/mL

* 溶解度測定はSelleck技術部門によって行われており、その他文献に示されている溶解度と差異がある可能性がありますが、同一ロットの生産工程で起きる正常な現象ですからご安心ください。

化学情報

分子量 361.44
化学式

C19H27N3O4

CAS No. 425386-60-3
保管
in solvent
別名 N/A

便利ツール

モル濃度計算器

モル濃度計算器

求めたい質量、体積または濃度を計算してください。

質量 (g) = 濃度 (mol/L) x 体積 (L) x 分子量 (g/mol)

モル濃度計算器方程式

  • 質量
    濃度
    体積
    分子量

*貯蔵液を準備するとき、常に、オンであるとわかる製品のバッチに特有の分子量を使って、を通してラベルとMSDS/COA(製品ページで利用可能な)。

希釈計算器

希釈計算器

貯蔵液を準備するために必要な希釈率を計算してください。Selleck希釈計算器は、以下の方程式に基づきます:

開始濃度 x 開始体積 = 最終濃度 x 最終体積

希釈の計算式

この方程式は、一般に略語を使われます:C1V1 = C2V2 ( 入力 出力 )

  • C1
    V1
    C2
    V2

常に貯蔵液を準備するとき、小びんラベルとMSDS/COA(オンラインで利用できる)で見つかる製品のバッチに特有の分子量を使ってください。

連続希釈計算器方程式

  • 連続希釈剤

  • 計算結果

  • C1=C0/X C1: LOG(C1):
    C2=C1/X C2: LOG(C2):
    C3=C2/X C3: LOG(C3):
    C4=C3/X C4: LOG(C4):
    C5=C4/X C5: LOG(C5):
    C6=C5/X C6: LOG(C6):
    C7=C6/X C7: LOG(C7):
    C8=C7/X C8: LOG(C8):
分子量計算器

分子量计算器

そのモル質量と元素組成を計算するために、合成物の化学式を入力してください:

総分子量:g/mol

チップス: 化学式は大文字と小文字の区別ができます。C10H16N2O2 c10h16n2o2

モル濃度計算器

質量 濃度 体積 分子量

臨床試験

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01035138 Completed Alzheimer''s Disease Eli Lilly and Company December 2009 Phase 3
NCT01035138 Completed Alzheimer''s Disease Eli Lilly and Company December 2009 Phase 3
NCT00762411 Completed Alzheimer''s Disease Eli Lilly and Company September 2008 Phase 3
NCT00762411 Completed Alzheimer''s Disease Eli Lilly and Company September 2008 Phase 3
NCT00594568 Completed Alzheimer''s Disease Eli Lilly and Company March 2008 Phase 3
NCT00594568 Completed Alzheimer''s Disease Eli Lilly and Company March 2008 Phase 3

技術サポート

ストックの作り方、阻害剤の保管方法、細胞実験や動物実験の際に注意すべき点など、製品を取扱う時に問い合わせが多かった質問に対しては取扱説明書でお答えしています。

Handling Instructions

他に質問がある場合は、お気軽にお問い合わせください。

  • * 必須

Gamma-secretaseシグナル伝達経路

Gamma-secretase Inhibitors with Unique Features

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細胞株 試験類型 濃度 培養時間 溶剤類型 活性叙述 PMID