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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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Purity: ≥98%
CZC-25146 is a potent and selective LRRK2 inhibitor. Leucine-rich repeat kinase-2 (LRRK2) mutations are the most important cause of familial Parkinson's disease. CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency.
| ln Vitro |
CZC-25146 (0.01-5 μM; 7 days) does not inhibit neuronal growth or cause cytotoxicity in human cortical neurons [1]. With an EC50 of about 100 nM, CZC-25146 (0.01-5 μM; 2 days) efficiently attenuates G2019S LRRK2-mediated toxicity in primary rodent neurons in a concentration-dependent manner [1]. Neurite abnormalities produced by LRRK2 G2019S in primary human neurons are rescued in a dose-dependent manner by CZC-25146 (0.06-1000 nM) [1]. Without compromising cell viability, CZC-25146 (14.3 and 28.6 μM; 48 hours) dramatically lowers allele Z (ATZ) polymer loading, which encodes mutant AAT, and restores AAT secretion in iPSC hepatocytes [3].
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| ln Vivo |
In mice overexpressing the human polymer ATZ, CZC-25146 (250 mg/kg; oral; 14 days) lowers the levels of ATZ polymer [3]. After injecting CZC-25146 intravenously into mice, the drug distributes broadly throughout the animal and demonstrates comparatively acceptable pharmacokinetic features (1 mg/kg intravenously; 5 mg/kg oral; single dosage).
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| Cell Assay |
Cytotoxicity assay[1]
Cell Types: human cortical neurons Tested Concentrations: 0.01, 0.1, 1 and 5 μM Incubation Duration: 7 days Experimental Results: Concentrations below 5 μM were not harmful to human cortical neurons when treated for 7 days in culture It produces cytotoxicity to neurons and does not hinder neuronal development. |
| Animal Protocol |
Animal/Disease Models: Male CD-1 mice[1]
Doses: 1 mg/kg, intravenous (iv) (iv)injection; 5 mg/kg orally. Doses: intravenous (iv) (iv)injection and oral administration; single dose Experimental Results: CZC-25146 in male CD-1 mice pharmacokinetic/PK/PK parameters [1]. iv (1 mg/kg) po (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 |
| References |
[1]. Ramsden N, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem Biol. 2011 Oct 21;6(10):1021-8.
[2]. Atashrazm F, et al. LRRK2 inhibitors and their potential in the treatment of Parkinson's disease: current perspectives. Clin Pharmacol. 2016 Oct 20;8:177-189. [3]. Deniz Kent, et al. Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency. |
| Molecular Formula |
C22H25N6O4FS
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|---|---|
| Molecular Weight |
488.5351
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| CAS # |
1191911-26-8
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| Related CAS # |
CZC-25146 hydrochloride;1330003-04-7
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| SMILES |
CS(=O)(NC1=CC=CC=C1NC2=NC(NC3=CC=C(N4CCOCC4)C=C3OC)=NC=C2F)=O
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 46 mg/mL (~94.16 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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