CZC-25146 是一种有效且具有口服活性的LRRK2抑制剂，对野生型 LRRK2 和突变型 LRRK2 G2019S 的IC50分别为 4.76 nM 和 6.87 nM。也抑制激酶 PLK4、GAK、TNK1、CAMKK2 和 PIP4K2C。CZC-25146 能在体外抑制突变 LRRK2 诱导的神经元损伤。CZC-25146 在小鼠体内表现出相对较好的药代动力学特性。CZC-25146 还能增加正常的 α-1 抗胰蛋白酶 (AAT) 的分泌，减少炎症细胞因子。CZC-25146 可用于帕金森病和肝病的研究。
| 生物活性 | CZC-25146 is a potent and orally activeLRRK2inhibitor withIC50values of 4.76 nM and 6.87 nM for wild-typeLRRK2and G2019SLRRK2, respectively. CZC-25146 inhibitsPLK4, GAK, TNK1, CAMKK2 and PIP4K2C as well. CZC-25146 prevents mutant LRRK2-induced injury of neuronsin vitro. 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 Parkinson's disease and liver diseases[1][2][3]. |
| IC50& Target | IC50: 4.76 nM (wild-type LRRK2), 6.87 nM (G2019S LRRK2)[1] |
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[1].
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 EC50of ~100 nM[1].
CZC-25146 (0.06-1000 nM) rescues LRRK2 G2019S-induced neurite defects in primary human neurons in a dose-dependent manner[1].
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[3].
Cell Cytotoxicity Assay[1] | 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. |
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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[3].
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[1].
| Animal Model: | Genetically modified male mice (6 weeks; over expressing human polymeric ATZ)[3] | | 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[1] | | 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[1].
| i.v. (1 mg/kg) | p.o. (5 mg/kg) | | CL (L/h/kg) | 2.3 | | | Vss(L/kg) | 5.4 | | | t1/2(h) | 1.6 | 1 | | tmax(h) | 0 | 0.25 | | Cmax(ng/mL) | 154 | 1357 | | AUClast(ng/mL·h) | 419 | 2878 | | AUCinf(ng/mL·h) | 434 | 2894 | | F (%) | | 133 |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : ≥ 46 mg/mL(94.16 mM) *"≥" means soluble, but saturation unknown. 配制储备液 | 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 |
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储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro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. 请依序添加每种溶剂： 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。 2. 请依序添加每种溶剂： 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。 *以上所有助溶剂都可在本网站选购。
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