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JNJ-61432059

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Chemical Structure| 2035814-50-5 同义名 : -
CAS号 : 2035814-50-5
货号 : A1149111
分子式 : C25H22FN5O2
纯度 : 99%+
分子量 : 443.473
MDL号 : MFCD32062672
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(112.75 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
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 (Kpu,u = 0.4) despite low plasma exposures (Cmax = 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 Tmax 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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.25mL

0.45mL

0.23mL

11.27mL

2.25mL

1.13mL

22.55mL

4.51mL

2.25mL
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.