CZC-25146|1191911-26-8|-陌孚医药/Medlife

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CZC-25146

目录号: PC16100 纯度: ≥98%

CAS No. :1191911-26-8

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PC16100-10mM (in 1mL DMSO)	10mM (in 1mL DMSO)	¥1705.20	请登录

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中文名称

CZC-25146

中文别名

(-)-丁子香烯氧化物;4-异丙基硫杂蒽酮;N-(2-(2-(2-甲氧基-4-吗啉苯基氨基)-5-氟嘧啶-4-基氨基)苯基)甲烷磺酰胺;CZC-25146

英文名称

CZC-25146

英文别名

N-(2-(2-(2-Methoxy-4-morpholinophenylamino)-5-fluoropyrimidin-4-ylamino)phenyl)methanesulfonamide;CZC25146;CZC-25146;N-(2-(5-fluoro-2-(2-methoxy-4-morpholinophenylamino)pyrimidin-4-ylamino)phenyl)methanesulfonamide;N-[2-[[5-Fluoro-2-[[2-methoxy-4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]amino]phenyl]methanesulfonamide

Cas No.

1191911-26-8

分子式

C₂₂H₂₅N₆O₄FS

分子量

488.54

包装储存

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

生物活性

CZC-25146 is a potent and orally active LRRK2 inhibitor with IC₅₀ values of 4.76 nM and 6.87 nM for wild-type LRRK2 and G2019S LRRK2, respectively. CZC-25146 inhibits PLK4, GAK, TNK1, CAMKK2 and PIP4K2C as well. CZC-25146 prevents mutant LRRK2-induced injury of neurons 体外研究. CZC-25146 exhibits relatively favorable pharmacokinetic properties in mice. CZC-25146 can increase normal α-1-antitrypsin (AAT) secretion and reduce inflammatory cytokines. CZC-25146 can be used to research Parkinsons disease and liver diseases.

性状

Solid

IC50 & Target[1][2]

IC₅₀: 4.76 nM (wild-type LRRK2), 6.87 nM (G2019S LRRK2)

体外研究(In Vitro)

CZC-25146 (0.01-5 μM; 7 days) does not cause cytotoxicity in human cortical neurons, nor blocking neuronal development.
CZC-25146 (0.01-5 μM; 2 days) potently attenuates G2019S LRRK2-mediated toxicity in primary rodent neurons in a concentration-dependent manner with an EC₅₀ of ~100 nM.
CZC-25146 (0.06-1000 nM) rescues LRRK2 G2019S-induced neurite defects in primary human neurons in a dose-dependent manner.
CZC-25146 (14.3 and 28.6 μM; 48 h) markedly reduces The mutant AAT encoded by the Z allele (ATZ) polymer load and restores AAT secretion in iPSC-Hepatocyte, without compromising cell viability.

Medlife has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Cytotoxicity Assay

Cell Line:	Human cortical neurons
Concentration:	0.01, 0.1, 1 and 5 μM
Incubation Time:	7 days
Result:	Did not cause cytotoxicity in human cortical neurons at concentrations below 5 μM over a seven-day treatment in culture, nor did it block neuronal development.

体内研究(In Vivo)

CZC-25146 (250 mg/kg; p.o.; 14 days) reduces the ATZ polymer levels in over expressing human polymeric ATZ mice.
CZC-25146 (1 mg/kg for i.v.; 5 mg/kg for p.o.; single dosage) exhibits relatively good pharmacokinetic properties and an extensive distribution throughout animal body following intravenous injection into mice.

Medlife has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:	Genetically modified male mice (6 weeks; over expressing human polymeric ATZ)
Dosage:	250 mg/kg
Administration:	p.o.; 14 days
Result:	Dramatically and reproducibly reduced the ATZ polymer levels with an overall reduction from 60% in the control group to 37%.

Animal Model:

Male CD-1 mice

Dosage:

1 mg/kg for i.v.; 5 mg/kg for p.o.

Administration:

i.v. and p.o.; single dosage

Result:

Pharmacokinetic Parameters of CZC-25146 in male CD-1 mice.

	i.v. (1 mg/kg)	p.o. (5 mg/kg)
CL (L/h/kg)	2.3
V_ss (L/kg)	5.4
t_1/2 (h)	1.6	1
t_max (h)	0	0.25
C_max (ng/mL)	154	1357
AUC_last (ng/mL·h)	419	2878
AUC_inf (ng/mL·h)	434	2894
F (%)		133

运输条件

Room temperature or refrigerated transportation.

储存方式

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

参考文献

[1]. Ramsden N, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinsons disease-related toxicity in human neurons. ACS Chem Biol. 2011 Oct 21;6(10):1021-8. [Information]

[2]. Atashrazm F, et al. LRRK2 inhibitors and their potential in the treatment of Parkinsons disease: current perspectives. Clin Pharmacol. 2016 Oct 20;8:177-189. [Information]

[3]. Deniz Kent, et al. Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency.

溶解度数据

体外研究:

DMSO : ≥ 46 mg/mL (94.16 mM)

* "≥" means soluble, but saturation unknown.

配制储备溶液

浓度溶剂体积质量	1 mg	5 mg	10 mg

1 mM	2.0469 mL	10.2346 mL	20.4692 mL
5 mM	0.4094 mL	2.0469 mL	4.0938 mL
10 mM	0.2047 mL	1.0235 mL	2.0469 mL

产品不同，其溶解度不同。建议根据产品选择合适的溶剂配制储备溶液；配成溶液后，建议分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，建议在 6 个月内使用，-20°C 储存时，建议在 1 个月内使用。

体内研究:

建议根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都建议先按照 体外研究 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

1.

建议依照次序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% saline
Solubility: ≥ 2.5 mg/mL (5.12 mM); Clear solution

此方案可获得 ≥ 2.5 mg/mL (5.12 mM，饱和度未知) 的澄清溶液。
以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。
将 0.9 g 氯化钠，完全溶解于 100 mL ddH?O 中，得到澄清透明的生理盐水溶液
2.

建议依照次序添加每种溶剂： 10% DMSO 90% corn oil
Solubility: ≥ 2.5 mg/mL (5.12 mM); Clear solution

此方案可获得 ≥ 2.5 mg/mL (5.12 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。
以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

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产品使用指南

Data Sheet

1：一般建议：溶解度为Medlife测试数据，可能与文献描述存在差异。这是由于生产工艺和批次不同产生的正常现象。为了使其更好的溶解，请用37℃加热试管并在超声波水浴中震动片刻。不同批次产品溶解度各有差异，仅做参考，具体以实验方案为准。

2：储存条件：粉末-20°C一般情况可以保存3年，溶于溶剂-80°C一般情况可以保存1年。不同产品及不同批次产品可能存在差异，请细致阅读产品信息，并辅助参考相关文献描述。

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