JNJ-54175446
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December 03, 2025
Understanding interspecies drug response variations between human and rodent P2X7 receptors.
(PubMed, Nat Commun)
- "Cryo-EM structures revealed two distinct PCP sub-pockets: PCP1, a rigid base pocket demanding precise steric complementarity with PSFL1191, and PCP2, a conserved middle cavity targeted by JNJ-54175446, a clinical candidate unaffected by species differences...In P2rx7A312V/A312V mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-type animals. Our findings establish the structural basis for interspecies pharmacological divergence in P2X7 modulation and highlight transgenic models as powerful tools for predicting therapeutic efficacy, thereby enabling more precise and efficient drug discovery."
Journal • Preclinical
October 10, 2025
Fire and Ice: From Early Trauma Through P2X7 Receptor-Mediated Neuroinflammation to Depression and Anxiety – a review
(ECNP 2025)
- "Novel brain-penetrant P2X7R antagonists, such as JNJ-54175446 and JNJ-55308942, are currently undergoing phase 2 clinical trials for depression, reflecting growing interest in the receptor's translational potential. This review highlights the intersection of P2X7R signalling, ELS, and psychiatric disorders, emphasizing both indirect pathways through chronic neuroinflammation and direct genetic associations via P2RX7 variants. By integrating findings across species and methodologies, the review underscores the significance of this receptor as a molecular mediator of stress vulnerability. Elucidating the interplay between P2X7R and early adversity is crucial, as it could pave the way for personalized interventions tailored to individuals with a history of trauma.Dora Torok is supported by EKÖP-2024-68."
Review • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • IL1B • IL6 • TNFA
July 17, 2025
Continuous-flow synthesis of 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridines towards key intermediates of clinical candidates JNJ-54175446 and zanvipixant (JNJ-55308942) with antidepressant activity.
(PubMed, RSC Adv)
- "Applying the optimized conditions, yields of 48% (58% regioselectivity) and 45% (91% regioselectivity) were achieved, respectively. The method ensures safe utilization of azide in the cycloaddition, and uses a safer oxidant for the elimination, offering a scalable and affordable alternative synthetic route."
Journal • CNS Disorders • Depression • Inflammation • Psychiatry
January 31, 2025
P2X7R antagonism suppresses long-lasting brain hyperexcitability following traumatic brain injury in mice.
(PubMed, Theranostics)
- "To test the anti-epileptogenic effects of P2X7R antagonism, mice were treated with brain-penetrant P2X7R antagonists JNJ-54175446 (30 mg/kg) or AFC-5128 (30 mg/kg) for 7 days post-CCI. Finally, P2X7R radioligand uptake after TBI correlated with seizure threshold at 3 weeks post-injury. Our results demonstrate the antiepileptogenic potential of P2X7R antagonism to prevent TBI-induced epilepsy and indicate that P2X7R-based PET imaging may be a useful diagnostic tool to identify people at risk of developing PTE."
Journal • Preclinical • CNS Disorders • Epilepsy • Vascular Neurology • CX3CR1
January 24, 2024
Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice.
(PubMed, Front Pharmacol)
- "Using telemetry-based continuous EEG recordings in mice, we demonstrate that spontaneous recurrent seizures in the intraamygdala kainic acid model are refractory to the common anti-seizure medicine levetiracetam. Using a combination of immunohistochemistry and ex vivo radiotracer assay, we find that JNJ-54175446-treated mice at the end of recordings display a reduction in astrogliosis and altered microglia process morphology within the ipsilateral CA3 subfield of the hippocampus, but no difference in P2X7 receptor surface expression. The present study extends the characterisation of the drug-resistance profile of the intraamygdala kainic acid model in mice and provides further evidence that targeting the P2X7 receptor may have therapeutic applications in the treatment of temporal lobe epilepsy."
Journal • Preclinical • CNS Disorders • Epilepsy • Inflammation • CA3
July 24, 2023
Characterization of the central nervous system penetrant and selective purine P2X7 receptor antagonist JNJ-54175446 in patients with major depressive disorder.
(PubMed, Transl Psychiatry)
- "In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1β release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT)."
Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • IL18 • IL1B
June 22, 2022
Antidepressant Trial With P2X7 Antagonist JNJ-54175446
(clinicaltrials.gov)
- P2 | N=142 | Active, not recruiting | Sponsor: CCTU-Core | Recruiting ➔ Active, not recruiting
Biomarker • Enrollment closed • CNS Disorders • Depression • Immunology • Inflammation • Major Depressive Disorder • Mood Disorders • Psychiatry
May 11, 2022
Antidepressant Trial With P2X7 Antagonist JNJ-54175446
(clinicaltrials.gov)
- P2 | N=142 | Recruiting | Sponsor: CCTU-Core | Trial completion date: Jun 2022 ➔ Jun 2024 | Trial primary completion date: Apr 2022 ➔ Dec 2023
Trial completion date • Trial primary completion date • CNS Disorders • Depression • Immunology • Inflammation • Major Depressive Disorder • Mood Disorders • Psychiatry
August 18, 2021
Antidepressant Trial With P2X7 Antagonist JNJ-54175446
(clinicaltrials.gov)
- P2; N=142; Recruiting; Sponsor: CCTU-Core; Trial completion date: Dec 2021 ➔ Jun 2022; Trial primary completion date: May 2021 ➔ Apr 2022
Biomarker • Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Immunology • Inflammation • Major Depressive Disorder • Mood Disorders • Psychiatry • MRI
March 18, 2021
Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer.
(PubMed, Purinergic Signal)
- "It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts."
Journal • Review • Immunology • Inflammation • Oncology
November 05, 2020
Antidepressant Trial With P2X7 Antagonist JNJ-54175446
(clinicaltrials.gov)
- P2; N=142; Recruiting; Sponsor: CCTU-Core; Suspended ➔ Recruiting
Biomarker • Clinical • Enrollment open • CNS Disorders • Depression • Immunology • Inflammation • Mood Disorders • Psychiatry
August 20, 2020
[VIRTUAL] PET imaging strategies for measurement of target engagement
(ACS-Fall 2020)
- "In blocking experiments with [18F]JNJ-64413739, tracer brain uptake in NHPs was reduced in a dose-dependent manner by a P2X7R antagonists JNJ-54175446 and receptor occupancies (RO) at different dose levels were calculated...A Phase 0 exploratory study of [18F]JNJ-64511070 was initiated to evaluate the safety of the tracer and to visually and quantitatively assess brain uptake and pharmacokinetics of [18F]JNJ-64511070 in healthy subjects. The initial clinical evaluation of [18F]JNJ-64511070 suggests that this tracer is a suitable candidate PET ligand for imaging AMPAR/γ8 TARP and supporting its use for clinical target engagement studies."
Immunology • IL1B
January 12, 2019
PET Imaging of the P2X7 Ion Channel with a Novel Tracer [F]JNJ-64413739 in a Rat Model of Neuroinflammation.
(PubMed, Mol Imaging Biol)
- "While further work is needed to study [F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [F]JNJ-64413739 as a potential PET tracer of central neuroinflammation."
Biomarker • Journal • Preclinical • Immunology
May 18, 2020
Antidepressant Trial With P2X7 Antagonist JNJ-54175446
(clinicaltrials.gov)
- P2; N=142; Suspended; Sponsor: CCTU-Core; Recruiting ➔ Suspended
Biomarker • Clinical • Trial suspension • CNS Disorders • Depression • Mood Disorders
February 09, 2019
Preclinical evaluation and non-human primate receptor occupancy study of F-JNJ-64413739, a novel PET radioligand for P2X7 receptors.
(PubMed, J Nucl Med)
- "PET ligands for the P2X7 receptor will be not only valuable to assess central target engagement of drug candidates, but also hold promise as surrogate markers of central neuroinflammation. Herein we describe the in vitro and in vivo evaluation of F-JNJ-64413739, an F-labelled PET ligand for imaging the P2X7 receptor in the brain."
Journal • Preclinical
April 07, 2020
Characterisation of the pharmacodynamic effects of the P2X7 receptor antagonist JNJ-54175446 using an oral dexamphetamine challenge model in healthy males in a randomised, double-blind, placebo-controlled, multiple ascending dose trial.
(PubMed, J Psychopharmacol)
- "Subjects (N = 64) were randomised to either JNJ-54175446 (50-450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy. Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect."
Clinical • Journal • PK/PD data
September 30, 2018
F-JNJ-64413739, a novel PET ligand for the P2X7 ion channel: radiation dosimetry, kinetic modeling, test-retest variability and occupancy of the P2X7 antagonist JNJ-54175446.
(PubMed, J Nucl Med)
- "F-JNJ-64413739 is a suitable selective PET ligand for quantification of P2X7R in human brain, and can be used for testing target engagement by brain permeable P2X7 antagonists, assist in guiding dose selection and provide insight into the expression of P2X7R in health and disease. Future studies are needed to determine whether P2X7 polymorphisms contribute to signal variability across subjects."
Journal
September 29, 2018
Clinical pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-54175446, a brain permeable P2X7 antagonist, in a randomised single-ascending dose study in healthy participants.
(PubMed, J Psychopharmacol)
- "Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1β release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed."
Clinical • Journal • PK/PD data
October 25, 2019
Translational Model-Informed Dose Selection for a Positron Emission Tomography (PET) Imaging Study of JNJ-54175446, a P2X7 Receptor Antagonist.
(PubMed, Clin Transl Sci)
- "Potency estimate for brain occupancy was generally comparable to that for the suppression of the provoked peripherical IL-1β release ex vivo, indicating that blood IL-1β release may be used as a surrogate of central occupancy for JNJ-54175446. Translational PK-PD modeling approach could be used for selecting optimal doses for human PET and other clinical studies."
Journal
October 17, 2019
Reduced Baseline Resting-State Alpha Power Reverses Following P2X7 Inhibition in Major Depression
(ACNP 2019)
- "JNJ-54175446 is a selective, brain penetrant P2X7 receptor antagonist being assessed for use in the treatment of mood disorders... In the MDD patients, alpha power at baseline was lower than alpha power in healthy volunteers in prefrontal and left temporal brain regions. Baseline alpha power correlated with illness severity and with baseline emotion processing biases in overlapping prefrontal areas. Lower alpha power at baseline and correlations with illness severity replicate findings in the literature2,3."
October 04, 2019
ATP: Antidepressant Trial With P2X7 Antagonist JNJ-54175446
(clinicaltrials.gov)
- P2; N=142; Recruiting; Sponsor: CCTU-Core
Biomarker • Clinical • New P2 trial
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