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| Targets |
The primary target of JNJ-42253432 is the P2X7 receptor, an ATP-gated ion channel predominantly expressed on immune cells (microglia, macrophages) and involved in neuroinflammation and inflammatory responses. P2X7 activation by extracellular ATP triggers the release of pro-inflammatory cytokines such as IL-1β and IL-18 via the NLRP3 inflammasome, and is implicated in various CNS disorders including Alzheimer's disease, multiple sclerosis, and depression. JNJ-42253432 acts as a potent antagonist, blocking P2X7-mediated signaling and inflammatory responses.
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| ln Vitro |
In vitro, JNJ-42253432 demonstrates high-affinity binding to P2X7 channels with pKi values of 9.1 for rat and 7.9 for human P2X7. This indicates potent and selective antagonism of the P2X7 receptor across species. The compound's ability to penetrate the central nervous system makes it particularly valuable for studying CNS targets. Its high affinity (pKi 9.1 for rat) suggests strong receptor binding and potent functional inhibition.
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| ln Vivo |
JNJ-42253432 occupies brain P2X7 channels in rats when given an ED50 of 0.3 mg/kg, which is 42 ng/ml as the mean plasma concentration. Because JNJ-42253432 antagonizes the serotonin transporter (SERT), which has an ED50 of 10 mg/kg occupied by SERT, it also raises serotonin levels in the rat brain[1].
In vivo, JNJ-42253432 occupies the brain P2X7 channel with an ED₅₀ of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/mL. This demonstrates excellent brain penetration and target engagement at low doses. The compound is orally active, making it suitable for convenient administration in preclinical studies. Its CNS penetration and potent P2X7 antagonism make it a valuable tool for studying neuroinflammation in vivo. |
| Enzyme Assay |
For P2X7 antagonists, standard cell-free binding assays involve radioligand displacement using [³H]- or [¹²⁵I]-labeled P2X7 ligands (such as [³H]-A-804598 or [³H]-JNJ-54175446) and membrane preparations from cells expressing recombinant rat or human P2X7 receptors. Various concentrations of the test compound are incubated with the radioligand and receptor membranes, and bound radioactivity is measured to determine pKi values.
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| Cell Assay |
For P2X7 antagonists, standard cellular assays measure the compound's ability to block P2X7-mediated signaling. Cells expressing recombinant human or rat P2X7 receptors (e.g., HEK293, U937, or primary microglia) are treated with the P2X7 agonist BzATP in the presence or absence of the test compound. Functional readouts include calcium influx (measured by fluorescent dyes), dye uptake (e.g., YO-PRO-1), or IL-1β release (measured by ELISA), with IC₅₀ values determined from concentration-response curves.
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| Animal Protocol |
For in vivo evaluation of CNS-penetrant P2X7 antagonists, standard animal models include neuroinflammation models such as LPS-induced neuroinflammation, transgenic Alzheimer's disease models, or experimental autoimmune encephalomyelitis (EAE). The compound is typically administered orally, and brain penetration is confirmed by measuring compound levels in brain tissue and plasma. Target engagement can be assessed by ex vivo receptor occupancy studies using radiolabeled tracers.
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| ADME/Pharmacokinetics |
JNJ-42253432 is an orally active, CNS-penetrant compound that occupies the brain P2X7 channel with an ED₅₀ of 0.3 mg/kg. The corresponding mean plasma concentration of 42 ng/mL indicates good exposure and brain penetration at low doses. As a high-affinity antagonist with pKi values of 9.1 (rat) and 7.9 (human), it would be expected to have favorable distribution to the CNS. Comprehensive PK studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
Detailed toxicology data for JNJ-42253432 is not provided in the available sources. As a CNS-penetrant compound targeting the P2X7 receptor, it would have undergone standard preclinical safety assessments including genotoxicity, hERG cardiac safety evaluation, and repeated-dose toxicity studies. P2X7 antagonism may modulate immune responses, and potential effects on peripheral immune function would need to be evaluated. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
JNJ-42253432 has the molecular formula C₂₂H₂₅F₃N₄O₃S and a molecular weight of 482.5 g/mol. It is a potent, selective, CNS-penetrant P2X7 antagonist with pKi values of 9.1 (rat) and 7.9 (human). The compound occupies the brain P2X7 channel with an ED₅₀ of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/mL. It is orally active and capable of penetrating the central nervous system. No regulatory approval has been identified.
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| Molecular Formula |
C28H38N4O
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| Molecular Weight |
446.627526760101
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| Exact Mass |
446.304
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| CAS # |
1428327-35-8
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| PubChem CID |
71625847
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| Appearance |
White to off-white solid powder
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| LogP |
4.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
634
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CC=CC2CN(C)CCC1=2)NCC1(CCCCC1)N1CCN(C2C=CC=CC=2)CC1
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| InChi Key |
DIKKTLPJDURHSW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H38N4O/c1-30-16-13-25-23(21-30)9-8-12-26(25)27(33)29-22-28(14-6-3-7-15-28)32-19-17-31(18-20-32)24-10-4-2-5-11-24/h2,4-5,8-12H,3,6-7,13-22H2,1H3,(H,29,33)
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| Chemical Name |
2-methyl-N-[[1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl]-3,4-dihydro-1H-isoquinoline-5-carboxamide
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| Synonyms |
JNJ42253432; JNJ 42253432; JNJ-42253432
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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 : ~100 mg/mL (~223.90 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.60 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 (5.60 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 25.0 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: ≥ 2.5 mg/mL (5.60 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 | 2.2390 mL | 11.1949 mL | 22.3899 mL | |
| 5 mM | 0.4478 mL | 2.2390 mL | 4.4780 mL | |
| 10 mM | 0.2239 mL | 1.1195 mL | 2.2390 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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