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| Targets |
The primary molecular target of LRRK2 inhibitor 1 is leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein kinase that has been implicated in both familial and sporadic Parkinson's disease. LRRK2 inhibitor 1 is a potent and selective LRRK2 inhibitor with an IC50 of 13 nM. The compound also inhibits DCLK1 kinase with an IC50 of 2.61 nM. LRRK2 inhibitor 1 has a pIC50 of 6.8 for LRRK2. By inhibiting LRRK2 kinase activity, the compound reduces LRRK2-mediated phosphorylation of its substrates, which is believed to contribute to the pathogenesis of Parkinson's disease. The compound's selectivity for LRRK2 over other kinases is an important feature for its potential therapeutic use.
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| ln Vitro |
In vitro studies demonstrate that LRRK2 inhibitor 1 is a potent and selective inhibitor of LRRK2 kinase activity. The compound has an IC50 of 13 nM against LRRK2 and also inhibits DCLK1 kinase with an IC50 of 2.61 nM. In cellular assays, LRRK2 inhibitor 1 reduces LRRK2 activity, as measured by decreased phosphorylation of LRRK2 substrates such as Rab proteins. The compound shows good cell permeability and potency in cell-based assays. In LRRK2-expressing cell lines, treatment with LRRK2 inhibitor 1 leads to reduced LRRK2 autophosphorylation and decreased phosphorylation of downstream targets. The compound's selectivity profile has been evaluated against a panel of kinases, confirming its specificity for LRRK2 and DCLK1. These in vitro activities support its use as a research tool for studying LRRK2 biology.
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| ln Vivo |
In vivo studies of LRRK2 inhibitor 1 have demonstrated its efficacy in animal models of Parkinson's disease. The compound is orally active, making it suitable for convenient administration. In preclinical studies, LRRK2 inhibitor 1 reduces LRRK2 activity in cells and animal models of Parkinson's disease. In rodent models, the compound has been shown to reduce LRRK2-mediated phosphorylation of substrates in the brain, demonstrating target engagement. The compound's oral bioavailability and brain penetration make it a promising candidate for further development as a Parkinson's disease therapeutic. In vivo protocols typically involve oral administration of LRRK2 inhibitor 1 at doses determined from pharmacokinetic studies. Endpoints include assessment of LRRK2 substrate phosphorylation, behavioral outcomes in Parkinson's disease models, and histopathological examination of brain tissues.
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| Enzyme Assay |
For LRRK2 kinase assays, the enzymatic activity of recombinant human LRRK2 is measured using a radiometric or fluorescence-based assay. Purified LRRK2 enzyme is incubated with varying concentrations of LRRK2 inhibitor 1 (typically 0.001-100 µM) in reaction buffer containing 50 mM HEPES (pH 7.5), 10 mM MgCl₂, 1 mM DTT, and 0.01% Triton X-100 at 30°C. The reaction is initiated by the addition of ATP and substrate (e.g., LRRKtide or a peptide substrate), and incubated for 30-60 minutes. For radiometric assays, [γ-³²P]-ATP is used, and the reaction product is spotted onto phosphocellulose filters, washed, and counted by scintillation. For fluorescence-based assays, ADP production is measured using a coupled enzyme assay or a fluorescence polarization assay. IC50 values are calculated from dose-response curves. For selectivity profiling, the compound is tested against a panel of kinases (e.g., DCLK1, other kinases) to assess selectivity.
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| Cell Assay |
For cellular assays, LRRK2-expressing cells (e.g., HEK-293 cells overexpressing LRRK2 or neuronal cells) are cultured in appropriate medium. Cells are seeded in 6-well or 96-well plates and treated with LRRK2 inhibitor 1 at varying concentrations (0.001-10 µM) for 1-4 hours. Cells are lysed in RIPA buffer with protease and phosphatase inhibitors. LRRK2 activity is assessed by measuring phosphorylation of LRRK2 substrates (e.g., Rab10, Rab12) by Western blot using phospho-specific antibodies. LRRK2 autophosphorylation is also assessed.
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| Animal Protocol |
For in vivo studies, adult mice or rats (6-8 weeks old) are used. LRRK2 inhibitor 1 is formulated in vehicle (e.g., 0.5% methylcellulose or 10% DMSO in PEG400) and administered orally at doses of 1-50 mg/kg, typically once daily for 1-14 days. For target engagement studies, animals are treated with the compound, and brain tissues are collected at various time points (1-24 hours after dosing). Brain lysates are prepared and analyzed for LRRK2 substrate phosphorylation by Western blot. For pharmacokinetic studies, blood and brain samples are collected at various time points for compound quantification by LC-MS. For behavioral studies in Parkinson's disease models, animals may be treated with LRRK2 inhibitor 1 for 2-4 weeks, and behavioral tests (rotarod, open field, pole test) are performed. For neurochemical studies, brain tissues are analyzed for dopamine and its metabolites by HPLC.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for LRRK2 inhibitor 1 indicate that it is orally active. The compound shows good oral bioavailability and brain penetration, which are important features for a Parkinson's disease therapeutic. The compound's pharmacokinetic profile supports once-daily dosing. Specific pharmacokinetic parameters, including half-life, Cmax, Tmax, and AUC, may be available from published studies but are not extensively reported in the public domain. The compound's favorable pharmacokinetic properties contribute to its potential as a drug candidate for Parkinson's disease.
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| Toxicity/Toxicokinetics |
Toxicological data for LRRK2 inhibitor 1 are limited, as the compound is a research tool. In preclinical studies, the compound has been shown to be well-tolerated at pharmacologically active doses. No acute toxicity, organ-specific toxicity, or mutagenicity data have been reported. As with all research compounds, appropriate safety precautions should be taken when handling LRRK2 inhibitor 1, including the use of personal protective equipment and work in a well-ventilated area.
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| References | |
| Additional Infomation |
LRRK2 inhibitor 1 (CAS 1802525-61-6) is a potent, selective, and orally active inhibitor of leucine-rich repeat kinase 2 (LRRK2) with an IC50 of 13 nM. It also inhibits DCLK1 kinase with an IC50 of 2.61 nM and has a pIC50 of 6.8 for LRRK2. The compound reduces LRRK2 activity in cells and animal models of Parkinson's disease. Its molecular formula is C₂₀H₂₃N₅O₄ with a molecular weight of 397.43. LRRK2 inhibitor 1 is a promising drug candidate for the treatment of Parkinson's disease and is used as a research tool for studying LRRK2 biology. It is strictly for research use only.
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| Molecular Formula |
C20H23N5O4
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| Molecular Weight |
397.427724123001
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| Exact Mass |
397.175
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| CAS # |
1802525-61-6
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| PubChem CID |
118286428
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| Appearance |
White to off-white solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
547
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1CCN(C(C2C=CC(=C(C=2)OC)NC2=NC(=C3C=CNC3=N2)OCC)=O)CC1
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| InChi Key |
OTTOCUYGSZUQOI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H23N5O4/c1-3-29-18-14-6-7-21-17(14)23-20(24-18)22-15-5-4-13(12-16(15)27-2)19(26)25-8-10-28-11-9-25/h4-7,12H,3,8-11H2,1-2H3,(H2,21,22,23,24)
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| Chemical Name |
[4-[(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methoxyphenyl]-morpholin-4-ylmethanone
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| HS Tariff Code |
2934.99.9001
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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 : ~62.5 mg/mL (~157.26 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.23 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 20.8 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: 2.08 mg/mL (5.23 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5162 mL | 12.5808 mL | 25.1617 mL | |
| 5 mM | 0.5032 mL | 2.5162 mL | 5.0323 mL | |
| 10 mM | 0.2516 mL | 1.2581 mL | 2.5162 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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