JNJ-61432059
目录号 : GC34638JNJ-61432059是具有口服活性的、选择性的AMPAR的负向调节剂,其对GluA1/γ-8的pIC50值为9.7。在老鼠的海马体中显示出具有时间和剂量依赖性的AMPA受体占用情况,在角膜点燃癫痫动物模型中显示出较强的保护作用。
Cas No.:2035814-50-5
Sample solution is provided at 25 µL, 10mM.
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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]. pIC50: 9.7 (AMPAR)[1].
[1]. Savall BM, 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.
Cas No. | 2035814-50-5 | SDF | |
Canonical SMILES | OC1CCN(C2=NC=CC3=C(C4=CC=C(NC(C5)=O)C5=C4)C(C6=CC=C(F)C=C6)=NN32)CC1 | ||
分子式 | C25H22FN5O2 | 分子量 | 443.47 |
溶解度 | DMSO: 50 mg/mL (112.75 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.2549 mL | 11.2747 mL | 22.5494 mL |
5 mM | 0.451 mL | 2.2549 mL | 4.5099 mL |
10 mM | 0.2255 mL | 1.1275 mL | 2.2549 mL |
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Discovery of Imidazo[1,2- a]pyrazines and Pyrazolo[1,5- c]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators
This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine 5 was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure-activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide 26, JNJ-61432059. Following oral administration, 26 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.
Characterizing the binding and function of TARP γ8-selective AMPA receptor modulators
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)-type glutamate receptors (AMPARs) are the predominant excitatory neurotransmitter receptors in the brain, where they mediate synaptic transmission and plasticity. Excessive AMPAR activation leads to diseases such as epilepsy. AMPAR properties are modulated by auxiliary proteins and foremost by the transmembrane AMPAR regulatory proteins (TARPs). These distribute in unique expression patterns across the brain, rendering AMPAR/TARP complexes promising targets for region-specific therapeutic intervention. TARP γ8 is predominantly expressed in the forebrain and is enriched in the hippocampus, a region associated with temporal lobe epilepsy. Recent high-throughput medicinal chemistry screens have identified multiple promising compounds that selectively target AMPARs associated with γ8 and hold promise for epilepsy treatment. However, how these modulators target the receptor complex is currently unknown. Here, we use a combination of ligand docking, molecular dynamics simulations, and electrophysiology to address this question. We identify a conserved oxindole isostere, shared between three structurally diverse modulators (LY-3130481, JNJ-55511118, and JNJ-61432059) as the major module engaging γ8 by an H-bond to Asn-172 (γ8). The remaining variable region of each molecule likely targets the receptor complex in ligand-selective modes. Functional data reveal parallels in the underlying modulatory action of two prominent compounds. This work will aid development of refined AMPAR epilepsy therapeutics and facilitate to uncover the mechanisms by which TARPs modulate the receptor.