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CAS No.: 425386-60-3

Semagacestat Catalog No. CSN16909

Synonyms: LY450139;LY-4501

Semagacestat is an inhibitor of γ-secretase. It inhibits Aβ42, Aβ38, Aβ40 and the Notch signaling with IC50 of 10 nM, 12 nM, 12.1 nM and 14.1 nM.

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靶点选择性

生物活性

实验方案

技术信息

生物活性

描述Semagacestat is a γ-secretase inhibitor with efficacy in multiple cellular and animal models, with IC50 values of 10.9nM, 12.1nM, 12nM, 14.1nM for secretion of Aβ42, Aβ40, Aβ38 and Notch, respectively, and EC50 value of 16nM forβ-CTF production. Exposure to Semagacestat at concentration ranging in 3.2, 16, 80, 2000, and 10,000 nM for 24 h led a concentration-dependent increase of β-CTF and α-CTF in H4 cells stably overexpressing human wild-type APP. It is regarded as a candidate drug for a causal therapy against Alzheimer's disease and showed blood-brain barrier permeability. Oral administration of semagacestat at dose of 1mg for 8 days significantly ameliorated spatial working memory deficits (shown by Y-maze) in Tg2576 mice (5.5-monthold) on day 1, but not on day 8. Both reduction of hippocampal Aβ42/Aβ40 by 22–23% and elevation of β-CTF by 162% could be observed in Tg2576 mice after dose of 10mg. A subcutaneous injection of semagacestat at dose of 5 mg/kg immediately after traumatic brain injury and once daily for 3 consecutive days post-traumatic brain injury attenuated neurotrauma and neurogenic acute lung injury in rats due to reducing the accumulation of hypertrophic microglia in the vicinity of the lesion.
细胞研究

Cell Data

Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
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
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

动物研究
剂量
Mice: 3 mg/kg - 30 mg/kg^[1] (p.o.); 1000 mg/kg^[4] (s.c. BID or p.o.) Guinea pig: 0.2 mg/kg- 60 mg/kg^[5] (p.o.)

给药途径
p.o., s.c.
临床研究
NCT号适应症或疾病临床期招募状态预计完成时间地点
NCT00594568 Alzheimer's Disease Phase 3 Completed - -
NCT01035138 Alzheimer's Disease Phase 3 Completed - -
NCT00594568 - - Completed - -
更多
参考文献

动物研究
剂量	Mice: 3 mg/kg - 30 mg/kg^[1] (p.o.); 1000 mg/kg^[4] (s.c. BID or p.o.) Guinea pig: 0.2 mg/kg- 60 mg/kg^[5] (p.o.)
给药途径	p.o., s.c.

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT00594568	Alzheimer's Disease	Phase 3	Completed	-	-
NCT01035138	Alzheimer's Disease	Phase 3	Completed	-	-
NCT00594568	-	-	Completed	-	-

[1] Mitani Y, Yarimizu J, et al. 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.
[2] Lanz TA, Karmilowicz MJ, et al. Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther. 2006 Nov;319(2):924-33. Epub 2006 Aug 18.
[3] Lin HJ, Hsu CC, et al. Gamma-Secretase Inhibitors Attenuate Neurotrauma and Neurogenic Acute Lung Injury in Rats by Rescuing the Accumulation of Hypertrophic Microglia. Cell Physiol Biochem. 2017;44(5):1726-1740.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.7667 mL
- 13.8337 mL
- 27.6675 mL
- 5 mM
- 0.5533 mL
- 2.7667 mL
- 5.5335 mL
- 10 mM
- 0.2767 mL
- 1.3834 mL
- 2.7667 mL

技术信息

CAS号

425386-60-3

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C19H27N3O4

运输

蓝冰

分子量

361.44

别名

LY450139;LY-4501

溶解度

DMSO	250.0 mg/mL (691.7 mM)
Water	insoluble

动物实验配方

0.5% methylcellulose+water

30 mg/mL

suspension

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