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| 1mg |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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Purity: ≥98%
JNJ-61432059 is a novel, potent, oral bioactive and selective negative modulator of AMPAR (α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors) associated with trans-membrane AMPAR regulatory protein (TARP) γ-8, with a pIC50 of 9.7 for GluA1/γ-8. It exhibits time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, resulting in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.
| ln Vitro |
When tested at 10 μM, JNJ-61432059 did not inhibit glutamate-induced calcium-flux in heterologous cells that coexpressed AMPARs with any TARP other than γ-8 (Supplementary Table 1). In addition, no cross-reactivity was noted when JNJ-61432059 was screened against a panel of 52 receptors, ion channels, and transporters using radioligand displacement assays (<50% inh @ 1 μM; Eurofins/Cerep, Poitiers, France).
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| ln Vivo |
Following oral administration, JNJ-61432059 exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.
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| Animal Protocol |
After oral dosing at 10 mg/kg in rats, JNJ-61432059 distributed into the brain (Kpu,u = 0.4) despite low plasma exposures (Cmax = 26 ng/mL) and high clearance (Cl = 57 mL/min/kg). [1]
Specifically, when JNJ-61432059 was incubated with hepatocytes for 4 h at 37 °C, the O-glucuronide was detected as the major metabolite in rat, but only as a minor metabolite in human, mouse, dog, and monkey hepatocytes. [1] This species-specific metabolism was further supported by mouse PK studies, in which JNJ-61432059 displayed improved clearance (40 mL/min/kg) and ∼80-fold higher plasma exposures (Cmax = 2037 ng/mL) compared to an equivalent dose in rat. Furthermore, when administered orally at 10 mg/kg,JNJ-61432059 showed high target engagement in mouse hippocampus, as measured by ex vivo autoradiography,5 with maximal receptor occupancy exceeding 90% at 1 h. [1] |
| References |
| Molecular Formula |
C25H22FN5O2
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|---|---|
| Molecular Weight |
443.472888469696
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| Exact Mass |
443.175
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| CAS # |
2035814-50-5
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| PubChem CID |
122656119
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| Appearance |
White to off-white solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
33
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| Complexity |
711
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C=CC(=CC=1)C1C(C2C=CC3=C(CC(N3)=O)C=2)=C2C=CN=C(N2N=1)N1CCC(CC1)O
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| InChi Key |
UWIJVELUZWBFEU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H22FN5O2/c26-18-4-1-15(2-5-18)24-23(16-3-6-20-17(13-16)14-22(33)28-20)21-7-10-27-25(31(21)29-24)30-11-8-19(32)9-12-30/h1-7,10,13,19,32H,8-9,11-12,14H2,(H,28,33)
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| Chemical Name |
5-[2-(4-fluorophenyl)-7-(4-hydroxy-1-piperidyl)pyrazolo[1,5-c]pyrimidin-3-yl]indolin-2-one.
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| Synonyms |
JNJ-61432059; JNJ 61432059; JNJ61432059;
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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 (~112.75 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.69 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 (4.69 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 20.8 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 | 2.2549 mL | 11.2747 mL | 22.5494 mL | |
| 5 mM | 0.4510 mL | 2.2549 mL | 4.5099 mL | |
| 10 mM | 0.2255 mL | 1.1275 mL | 2.2549 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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