N-((4-(4-phenylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)methyl)-2-(phenylthio)nicotinamide

Product NameN-((4-(4-phenylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)methyl)-2-(phenylthio)nicotinamide
CAS1428327-31-4
MFC28H32N4O2S
MW488.64
EINECS
MOL File1428327-31-4.mol

Chemical Properties

storage temp.	2-8°C
solubility	DMF:30.0(Max Conc. mg/mL);61.39(Max Conc. mM) DMSO:59.62(Max Conc. mg/mL);122.01(Max Conc. mM) DMSO:PBS (pH 7.2) (1:3):0.25(Max Conc. mg/mL);0.51(Max Conc. mM) Ethanol:12.5(Max Conc. mg/mL);25.58(Max Conc. mM)
form	powder
color	white to beige
InChI	1S/C28H32N4O2S/c33-26(25-12-7-15-29-27(25)35-24-10-5-2-6-11-24)30-22-28(13-20-34-21-14-28)32-18-16-31(17-19-32)23-8-3-1-4-9-23/h1-12,15H,13-14,16-22H2,(H,30,33)
InChIKey	XREFXUCWSYMIOG-UHFFFAOYSA-N
SMILES	O=C(NCC1(CCOCC1)N2CCN(C3=CC=CC=C3)CC2)C4=CC=CN=C4SC5=CC=CC=C5

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Description

JNJ-47965567 is a selective antagonist of the purinergic receptor P2X subtype 7 (P2X₇), a ligand-gated ion channel. Activation of P2X receptors by BzATP induces calcium flux, which is reduced by JNJ-47965567 in 1321N1 cells transfected with recombinant P2X₇ human, macaque, dog, rat, or mouse protein with pIC₅₀s of 8.3, 8.6, 8.5, 7.2, or 7.5, respectively. JNJ-47965567 suppresses neonatal hypoxia-induced seizures in mice and has some anticonvulsant properties in rats. It also reduces spontaneous seizures in epileptic mice even after treatment is stopped.

Uses

2-(Phenylthio)-N-[[tetrahydro-4-(4-phenyl-1-piperazinyl)-2H-pyran-4-yl]methyl]-3-pyridinecarboxamide is a potent and selective human P2X7 antagonist.

Biochem/physiol Actions

JNJ-47965567 is a potent P2X7 antagonist with high affinity for the rat receptor (pKi = 8.7). It is centrally available after systemic injection with a superior brain:plasma distribution compared to other available P2X7 antagonists. JNJ-47965567 was shown to suppress epileptic seizures in a mouse model of epilepsy. It appears to have a disease modifying effect since spontaneous seizure rates did not increase once treatment with JNJ-477965567 was stopped.

in vivo

JNJ-47965567 (30-100 mg/kg; s.c.) attenuates IL-1β release induced by Bz-ATP^[1].
JNJ-47965567 (30 mg/kg) attenuates amphetamine-induced hyperactivity and exhibits modest, yet significant efficacy in the rat model of neuropathic pain^[1].

Animal Model:	Male Sprague Dawley rats^[1]
Dosage:	30 mg/kg, 100 mg/kg
Administration:	Subcutaneous injection; 30 minutes prior to Bz-ATP infusion
Result:	Significantly attenuated IL-1β release at 100 mg/kg, with no effect at 30 mg/kg dose group.

IC 50

P2X7 Receptor

storage

Store at +4°C

References

[1] ANINDYA BHATTACHARYA. Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567[J]. British Journal of Pharmacology, 2013, 170 3: 624-640. DOI: 10.1111/bph.12314
[2] NATALIA RODRIGUEZ-ALVAREZ . Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice[J]. Neuropharmacology, 2017, 116: Pages 351-363. DOI: 10.1016/j.neuropharm.2017.01.005
[3] WOLFGANG FISCHER. Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models.[J]. PLoS ONE, 2016: e0156468. DOI: 10.1371/journal.pone.0156468
[4] ALBA JIMENEZ-PACHECO. Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy.[J]. Journal of Neuroscience, 2016, 36 22: 5920-5932. DOI: 10.1523/jneurosci.4009-15.2016

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