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| Targets |
Adaptor protein-2 associated kinase 1 (AAK1). LP-935509 also inhibits BMP2-inducible kinase (BIKE) with an IC50 of 14 nM and cyclin G-associated kinase (GAK) with an IC50 of 0.32 μM. It is an ATP-competitive inhibitor with a Ki of 0.9 nM for AAK1.
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| ln Vitro |
LP-935509 has an IC50 value of 2.8 ± 0.4 nM for μ2 phosphorylation inhibition and an IC50 value of 3.3 ± 0.7 nM for phosphorylation of peptides generated from μ2 protein[1]. The reduction of SARS-CoV-2 S-RBD internalization into host cells is demonstrated by LP-935509 in a dose-dependent manner [2].
LP-935509 inhibits μ2 phosphorylation with an IC50 of 2.8 ± 0.4 nM and inhibits phosphorylation of a peptide derived from the μ2 protein with an IC50 of 3.3 ± 0.7 nM. At 1 μM, it reduces phosphorylation of the synaptic vesicle regulator AP2 complex subunit μ-1 (AP2M1) in SH-SY5Y neuroblastoma cells. The compound exhibits dose-dependent inhibition of SARS-CoV-2 S-RBD internalization into host cells. |
| ln Vivo |
The oral single-dose medication LP-935509 (0–60 mg/kg) dramatically lowers pain behaviors [1]. ?In a CCI model, oral LP-935509 (0.1–30 mg/kg; single dosage) reverses thermal hyperalgesia in a dose-dependent manner [1]. ?LP-935509 (intravenous 1 mg/kg or oral 10 mg/kg once) has a 3.6-hour plasma half-life and 100% oral bioavailability [1].
LP-935509 (0-60 mg/kg; p.o., single) causes a robust reduction in pain behavior in male C57BL/6J mice with spinal nerve ligation injury. It causes a dose-dependent reversal of thermal hyperalgesia in the chronic constriction injury (CCI) model in rats. LP-935509 significantly reduces the number of formalin-induced flinches in mice at doses of 10, 30, and 60 mg/kg. |
| Enzyme Assay |
In vitro enzyme assays for LP-935509 involve measuring the inhibition of AAK1 kinase activity using peptide substrates. AAK1 is incubated with ATP, a peptide substrate derived from μ2 protein, and various concentrations of LP-935509. Phosphorylation of the peptide is measured using radioactive or fluorescent detection methods. IC50 values (3.3 nM) and Ki values (0.9 nM) are determined from concentration-response curves.
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| Cell Assay |
In vitro cellular assays for LP-935509 involve treating SH-SY5Y neuroblastoma cells with the compound and measuring phosphorylation of AP2M1, a physiological substrate of AAK1. Cells are treated with various concentrations of LP-935509, and AP2M1 phosphorylation is assessed by Western blot using phospho-specific antibodies. The compound's ability to inhibit AAK1-mediated phosphorylation in cells is demonstrated.
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| Animal Protocol |
Animal/Disease Models: Male C57BL/6J mice (with SNL (spinal nerve ligation) injury, n=8-10 male mice per group) [1]
Doses: 0, 10, 30 and 60mg/kg (10ml/kg) Route of Administration: PO, Single Outcome: Produced a dose-dependent reduction in stage II paw withdrawal that was Dramatically lower than in vehicle-treated animals; demonstrated a dose-dependent reversal of mechanical allodynia; resulted in a substantial reduction in pain behaviors. Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (CCI (chronic constriction injury) operated rat) [1] Doses: 0, 0.1, 0.3, 1, 3, 10 or 30 mg/kg Route of Administration: po (po (oral gavage)) daily Two, 5 consecutive day Experimental Results: Produced dose-dependent reversal of thermal hyperalgesia, cold hyperalgesia, mechanical hyperalgesia, and mechanical hyperalgesia in CCI animals. Reversal of behavioral deficits, ED50 values range from 2 mg/kg to 10 mg/kg. Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat[1] Doses: 1 mg/kg (IV), 10 mg/kg (PO) Route of Administration: IV, PO; once (pharmacokinetic/PK/PK analysis) Experimental Results: Oral bioavailability The conc In vivo animal studies for LP-935509 typically involve administration to rodent models of neuropathic pain. The compound is administered orally, and pain behavior is assessed using measures such as paw flinches, thermal hyperalgesia, and mechanical allodynia. Efficacy is evaluated by measuring the reduction in pain-related behaviors compared to vehicle-treated animals. |
| ADME/Pharmacokinetics |
LP-935509 has 100% oral bioavailability and a plasma half-life of 3.6 hours following IV (1 mg/kg) or oral (10 mg/kg) administration. It is a brain-penetrant compound, making it suitable for the treatment of central nervous system disorders. The compound is orally active and has a molecular weight of 396.44.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies of LP-935509 are limited. The compound is a selective AAK1 inhibitor that has been investigated for the treatment of neuropathic pain. It shows selectivity for AAK1 and BIKE over opioid and adrenergic receptors. Comprehensive toxicological evaluation is needed before clinical development.
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| References | |
| Additional Infomation |
LP-935509 is an orally active, potent, selective, ATP-competitive, and brain-penetrant inhibitor of adaptor protein-2 associated kinase 1 (AAK1) with an IC50 of 3.3 nM and a Ki of 0.9 nM. It has been investigated for the treatment of neuropathic pain. LP-935509 reduces pain behavior in rodent models of neuropathic pain and has 100% oral bioavailability. It is a valuable research tool for studying the role of AAK1 in pain and other neurological disorders.
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| Molecular Formula |
C20H24N6O3
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| Molecular Weight |
396.442963600159
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| Exact Mass |
396.191
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| Elemental Analysis |
C, 60.59; H, 6.10; N, 21.20; O, 12.11
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| CAS # |
1454555-29-3
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| Related CAS # |
1454555-29-3;
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| PubChem CID |
86697436
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.1
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
556
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
GOOYSJIWTIHOGW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H24N6O3/c1-14(2)29-20(27)25-11-9-24(10-12-25)17-6-8-26-18(23-17)16(13-22-26)15-5-4-7-21-19(15)28-3/h4-8,13-14H,9-12H2,1-3H3
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| Chemical Name |
propan-2-yl 4-[3-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate
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| Synonyms |
LP-935509 LP 935509 LP935509
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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 : ~50 mg/mL (~126.12 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.25 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 (5.25 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (5.25 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 | 2.5224 mL | 12.6122 mL | 25.2245 mL | |
| 5 mM | 0.5045 mL | 2.5224 mL | 5.0449 mL | |
| 10 mM | 0.2522 mL | 1.2612 mL | 2.5224 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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