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CAS No.: 1227163-84-9

AZD3839 Catalog No. CSN19061

Synonyms: AZD-3839 Free Base

AZD3839 is an inhibitor of BACE1 with IC50 of 23.6 uM.

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实验方案

技术信息

生物活性

描述BACE1 (β-site amyloid precursor protein cleaving enzyme1) is one of the key enzymes involved in the processing of APP and formation of Aβ. AZD3839 is a potent and selective BACE-1 inhibitor with Ki value of 26.1 for affinity to hBACE1 in TR-FRET assay, demonstrating much less selectivity against hBACE2 hCathepsin D with Ki values of 372.4nM and >25,000nM, respectively. Exposure to AZD3839 led to reduced Aβ40 release with IC50 values of 4.8nM, 32.2nM and 50.9nM for modified and wild-type human SH-SY5Y cells, mouse N2A and mouse primary neurons, and inhibited sAPPβ release with IC50 value of 16.7nM for human SH-SY5Y cells. Reduction of brain Aβ40 by ~30% and ~50% achieved by oral administration of AZD3839 to C57BL/6 mice at dose of 35mg/kg and 69 mg/kg, respectively, after 1.5h. The reduction of brain Aβ42 followed the similar pattern. The access of AZD3839 into the CNS in mice is unrestricted shown by the average ratio of 0.7 between free concentrations in plasma and brain. Inhibition of BACE1 by AZD3839 intraperitoneal administrated to J20-TG-AD mice (transgenic mouse model of AD) rescued the abnormal early electrophysiological phenotype of less theta-gamma cross-frequency coupling.
作用机制AZD3839 binds in the active site of BACE1 in a flap-open conformation with the pyridine nitrogen located close to the S2 pocket, interacting with Trp-76 via an important hydrogen bond.^[1]
细胞研究

Cell Data

Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
CHO cells	-	Function assay	-	Inhibition of human ERG expressed in CHO cells by IonWorks assay, IC50=4.8 μM	22924815
SH-SY5Y cells	-	Function assay	16 h	Inhibition of BACE1 in human SH-SY5Y cells assessed as inhibition of sAPPbeta release after 16 hrs by immunoassay, IC50=0.0167 μM	22924815

动物研究
剂量
Mice: 35 mg/kg, 69 mg/kg^[1] (p.o.) Cynomolgus monkeys: 2.4 mg/kg - 8.6 mg/kg^[1] (i.v.)

给药途径
p.o., i.v.
临床研究

动物研究
剂量	Mice: 35 mg/kg, 69 mg/kg^[1] (p.o.) Cynomolgus monkeys: 2.4 mg/kg - 8.6 mg/kg^[1] (i.v.)
给药途径	p.o., i.v.

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT01348737	Alzheimer's Disease ... more >> Safety Tolerability Blood Concentration Healthy Volunteers Collapse <<	Phase 1	Completed	-	United Kingdom ... more >> Research Site London, United Kingdom Collapse <<

参考文献

[1] Jeppsson F, Eketjäll S, et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012 Nov 30;287(49):41245-57.
[2] Mondragón-Rodríguez S, Gu N, et al. Alzheimer's Transgenic Model Is Characterized by Very Early Brain Network Alterations and β-CTF Fragment Accumulation: Reversal by β-Secretase Inhibition. Front Cell Neurosci. 2018 May 8;12:121.

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
- 2.3180 mL
- 11.5898 mL
- 23.1797 mL
- 5 mM
- 0.4636 mL
- 2.3180 mL
- 4.6359 mL
- 10 mM
- 0.2318 mL
- 1.1590 mL
- 2.3180 mL

技术信息

CAS号

1227163-84-9

储存条件

粉末: Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C24H16F3N5

运输

蓝冰

分子量

431.41

别名

AZD-3839 Free Base

溶解度

DMSO	86.0 mg/mL (199.3 mM)
Water	Insoluble
Ethanol	86.0 mg/mL (199.3 mM) warming

动物实验配方

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