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CAS No.: 2035814-50-5

JNJ-61432059 Catalog No. CSN24076

JNJ-61432059 is an oral active and selective negative modulator of AMPAR associated with trans-membrane AMPAR regulatory protein (TARP) γ-8, with a pIC50 of 9.7 for GluA1/γ-8. 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[1].

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

描述AMPA receptors (AMPARs) are assembled as tetramers of pore-forming subunits (GluA1−GluA4) together with a host of accessory proteins that work in concert to regulate receptor trafficking and pharmacology. Most, if not all, AMPARs are associated with transmembrane AMPAR regulatory proteins (TARPs), which are classified by sequence homology and function as Type I (γ-2, γ-3, γ-4, γ-8) or Type II (γ-5, γ-7)^[2]. JNJ-61432059 is an oral active and selective negative modulator of AMPAR associated with trans-membrane AMPAR regulatory protein (TARP) γ-8. In a FLIPR assay using HEK-293 cells expressing a human GluA1o-γ-8 fusion construct, JNJ-61432059 has a pIC₅₀ value of 9.7 for GluA1/γ-8^[2]. JNJ-61432059 showed inhibition of CYPs 2C8 and 2C9 at lower concentrations (IC₅₀s = 3.0 and 1.9 μM, respectively)^[2]. After oral dosing at 10 mg/kg in rats, JNJ-61432059 distributed into the brain (K_pu,u = 0.4) despite low plasma exposures (C_max = 26 ng/ml) and high clearance (Cl = 57 ml/min/kg). When JNJ-61432059 was incubated with hepatocytes for 4 h at 37 °C, the O-glucuronide was detected as the major metabolite in rat. When administered orally at 10 mg/kg, JNJ-61432059 showed high target engagement in mouse hippocampus, as measured by ex vivo autoradiography, with maximal receptor occupancy exceeding 90% at 1 h. The plasma and brain exposures at T_max were highly linear over a wide dose range, and the receptor occupancy was well described by a Hill function with ED₅₀ = 2.9 ± 0.7 mg/kg^[2].
动物研究
剂量
Mice: 10 mg/kg^[1] (p.o.)

给药途径
p.o.

动物药代数据
Animal Mice^[1] Rats^[1]
Dose 10 mg/kg 10 mg/kg
Administration p.o. p.o.
C_max 2037 ng/ml 26 ng/ml
CL 40 ml/min/kg 57 ml/min/kg
参考文献

[1] Savall BM, Wu D, et al. Discovery of Imidazo[1,2-a]pyrazines and Pyrazolo[1,5-c]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators. ACS Med Chem Lett. 2018 Dec 26;10(3):267-272.
[2] Savall BM, Wu D, Swanson DM, Seierstad M, Wu N, Vives Martinez J, García Olmos B, Lord B, Coe K, Koudriakova T, Lovenberg TW, Carruthers NI, Maher MP, Ameriks MK. Discovery of Imidazo[1,2-a]pyrazines and Pyrazolo[1,5-c]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators. ACS Med Chem Lett. 2018 Dec 26;10(3):267-272. doi: 10.1021/acsmedchemlett.8b00599. PMID: 30891124; PMCID: PMC6421542.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.2549 mL
- 11.2746 mL
- 22.5493 mL
- 5 mM
- 0.4510 mL
- 2.2549 mL
- 4.5099 mL
- 10 mM
- 0.2255 mL
- 1.1275 mL
- 2.2549 mL

技术信息

CAS号

2035814-50-5

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C25H22FN5O2

运输

蓝冰

分子量

443.47

别名

溶解度

DMSO	90.0 mg/mL (202.9 mM)
Water	insoluble

动物实验配方

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