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Semagacestat (LY450139)

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.

Semagacestat (LY450139)化学構造

CAS No. 425386-60-3

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 37000 国内在庫あり
JPY 25500 国内在庫あり
JPY 145500 国内在庫あり
JPY 448500 国内在庫なし(納期7~10日)

代表番号: 045-509-1970|電子メール：[email protected]
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Semagacestat (LY450139)関連製品

Secretase阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
CHO cells Function assay Inhibition of gamma-secretase in CHO cells assessed expressing APPSw assessed as inhibition of amyloid beta(1 to x) secretion after overnight incubation by ELISA, ED50=0.015 μM 23713656
human SH-SY5Y cells Function assay Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells, IC50=0.038 μM 19694467
African green monkey CV1 cells Function assay Inhibition of gamma-secretase expressed in african green monkey CV1 cells coexpressing Gal4 DNA-binding/transactivation domain assessed as inhibition of notch processing by luciferase reporter assay, IC50=0.31623 μM 20056541
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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.
Targets
Aβ42 [1]
(H4 human glioma cells)		 Aβ38 [1]
(H4 human glioma cells)		 Aβ40 [1]
(H4 human glioma cells)		 Notch [1]
(H4 human glioma cells)
10.9 nM 12.0 nM 12.1 nM 14.1 nM
In Vitro
In vitro 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]
Kinase Assay 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.
細胞実験 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.
In Vivo
In Vivo 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]
動物実験 動物モデル Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L)
投与量 ~30 mg/kg
投与経路 Orally administered once daily
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
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
NCT00594568 Completed
Alzheimer''s Disease
Eli Lilly and Company
 March 2008 Phase 3
NCT00765115 Completed
Alzheimer Disease
Eli Lilly and Company
 July 2006 Phase 1

化学情報

分子量 361.44 化学式

C19H27N3O4
CAS No. 425386-60-3 SDF Download Semagacestat (LY450139) SDFをダウンロードする
Smiles CC(C)C(C(=O)NC(C)C(=O)NC1C2=CC=CC=C2CCN(C1=O)C)O
保管

In vitro
Batch:

DMSO : 73 mg/mL ( (201.96 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : 41 mg/mL

Water : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

mg/kg g μL 匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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