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LY2886721
LY2886721 is a BACE inhibitor used for the treatment of Alzheimer's Disease. Phase 1/2.
CAS No. 1262036-50-9
文献中Selleckの製品使用例（17）
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LY2886721関連製品
シグナル伝達経路
BACE阻害剤の選択性比較
生物活性
| 製品説明 | LY2886721 is a BACE inhibitor used for the treatment of Alzheimer's Disease. Phase 1/2. | ||||
|---|---|---|---|---|---|
| Targets |
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| In Vitro | ||||
| In vitro | LY2886721 is an oral, small molecule of β-site amyloid protein cleaving enzyme (BACE) inhibitor with the potential to inhibit the synthesis of β-amyloid and thereby to slow the clinical progression of AD. [1] LY2886721 can also targetγ-secretase to nhibit the synthesis of β-amyloid[2]. LY2886721 inhibits recombinant hBACE1 with an IC50 of 20.3 nM. In cellular assays, LY2886721 inhibits Abeta with an IC50 of 18.7 nM and 10.7 nM, HEK293Swe and PDAPP neuronal culture, respectively[3]. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Assessment of LY2886721 activity against hBACE2 demonstrates an IC50 of 10.2 nM. Assessment of LY2886721 activity against cathepsin D, pepsin, renin, or other important aspartyl proteases shows essentially no inhibition (IC50 >100,000 nM), suggesting that activity against these common aspartyl proteases is unlikely to be significant[4]. | |||
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| 細胞実験 | 細胞株 | HEK293 cells | ||
| 濃度 | -- | |||
| 反応時間 | Overnight exposure | |||
| 実験の流れ | A human embryonic kidney cell line (HEK293) stably expressing APP751cDNA containing a Swedish mutation (HEK293Swe) was exposed to increasing concentrations of LY2886721 and the amount of amyloid β1–40 (Aβ1-40) and Aβ1-42 measured in the media as an index of BACE1 inhibition. Compound cytotoxicity was assessed using a CellTiter96 Aqueous Non-Radioactive Cell Proliferation assay |
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| In Vivo | ||
| In Vivo | Oral administration of LY2886721 to PDAPP mice produces dose-dependent reductions in brain Abeta, C99 and sAPPbeta. Brain Abeta levels are decreased ∼20%-65% relative to vehicle-treated groups three hours after a 3-30 mg/kg dose of LY2886721. Brain C99 and sAPPb levels also are reduced in a dose-dependent manner consistent with BACE1 inhibition in vivo. The pharmacodynamic responses to LY2886721 persists out to 9 hours post dose in brains of PDAPP mice. Pharmacodynamic studies in beagle dog reveal robust and sustained reductions in plasma Abeta following 1 mg/kg LY2886721 dosing. Central effects of BACE1 inhibition in dog are manifested by a 50% reduction in CSF Abeta at 9 hours after a 0.5 mg/kg dose of LY2886721[3]. The geometric mean terminal elimination t1/2 is determined to be 17.2 h (range 8.19-36.3 h). The geometric mean apparent oral clearance is 34.8 L/h (38% CV) and the apparent volume of distribution during the terminal phase was 863 L (56% CV) across dose levels. LY2886721 is freely permeable across the blood-brain barrier[4]. | |
|---|---|---|
| 動物実験 | 動物モデル | young PDAPP transgenic mice |
| 投与量 | 1.5 mg/kg | |
| 投与経路 | by oral gavage | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01807026 | Completed | Alzheimer Disease|Healthy Volunteers |
Eli Lilly and Company |
March 2013 | Phase 1 |
| NCT01534273 | Completed | Healthy Volunteers |
Eli Lilly and Company |
February 2012 | Phase 1 |
| NCT01367262 | Completed | Healthy Volunteers |
Eli Lilly and Company |
June 2011 | Phase 1 |
| NCT01227252 | Completed | Alzheimer''s Disease |
Eli Lilly and Company |
December 2010 | Phase 1 |
| NCT01133405 | Completed | Alzheimer''s Disease |
Eli Lilly and Company |
June 2010 | Phase 1 |
化学情報
| 分子量 | 390.41 | 化学式 | C18H16F2N4O2S |
| CAS No. | 1262036-50-9 | SDF | Download LY2886721 SDFをダウンロードする |
| Smiles | C1C2CSC(=NC2(CO1)C3=C(C=CC(=C3)NC(=O)C4=NC=C(C=C4)F)F)N | ||
| 保管 | |||
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In vitro |
DMSO : 35 mg/mL ( (89.64 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。) Water : Insoluble Ethanol : Insoluble |
モル濃度計算器 |
|
in vivo Add solvents to the product individually and in order. |
投与溶液組成計算機 | ||||
実験計算
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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