Efficacy and Safety of CE-224,535, an Antagonist of P2X<sub>7</sub>Receptor, in Treatment of Patients with Rheumatoid Arthritis Inadequately Controlled by Methotrexate

Stock, Thomas; Bloom, Bradley J.; Wei, Nathan; Ishaq, Saliha; Park, Won; Wang, Xin; Gupta, Pankaj; Mebus, Charles A.

doi:10.3899/jrheum.110874

Cited by 211 publications

(160 citation statements)

References 31 publications

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“…Our previous publication with the P2X7 antagonist JNJ-47965567 demonstrated a transient but modest efficacy in neuropathic pain (Bhattacharya et al, 2013). Our data (modest efficacy with JNJ-47965567 to no effect in this study with JNJ-42253432), along with the two failed clinical trials in rheumatoid arthritis (Keystone et al, 2012;Stock et al, 2012) using P2X7 antagonists, raise this dilemma of the utility of P2X7 antagonists as analgesics (Bhattacharya et al, 2011). Whether P2X7 antagonism has therapeutic benefits in CNS disorders, such as in neuropsychiatry and neurodegeneration, remains clinically untested.…”

Section: Discussionmentioning

confidence: 48%

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Lord

Aluisio

Shoblock

et al. 2014

J Pharmacol Exp Ther

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In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1b. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pK i 9.1 6 0.07) and human (pK i 7.9 6 0.08) P2X7 channel. The compound blocked the ATPinduced current and Bz-ATP [29(39)-O-(4-benzoylbenzoyl)adenosine-59-triphosphate tri(triethylammonium)]-induced release of IL-1b in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED 50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1b induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED 50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the a-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.

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Section: Discussionmentioning

confidence: 48%

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Lord

Aluisio

Shoblock

et al. 2014

J Pharmacol Exp Ther

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“…The purinergic antagonists are being actively studied for their therapeutic potential and have been demonstrated to be safe in clinical trials testing P2X7 antagonists in the treatment of rheumatoid arthritis (including trials AZD9056, CE-224,535, and GSK1482160) (48)(49)(50)(51)(52). We postulate that the development of targeted therapies that block these signaling pathways may provide simultaneous treatment of HIV-1 infection, the chronic inflammation associated with HIV-1 infection, and, possibly, the associated long-term sequelae, including neurotoxic effects (53).…”

Section: Discussionmentioning

confidence: 99%

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Swartz

Esposito

Durham

et al. 2014

J Virol

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Human immunodeficiency virus type 1 (HIV-1) infection is chronic and presently still incurable. Antiretroviral drugs effectively suppress replication; however, persistent activation of inflammatory pathways remains a key cause of morbidity. Recent studies proposed that purinergic signaling is required for HIV-1 infection. Purinergic receptors are distributed throughout a wide variety of tissue types and detect extracellular ATP as a danger signal released from dying cells. We have explored how these pathways are involved in the transmission of HIV-1 from cell to cell through virological synapses. Infection of CD4 ؉ T lymphocytes with HIV-1 in the presence of an inhibitor of P2X receptors effectively inhibited HIV-1 infection through both cell-free and cellto-cell contact in a dose-dependent manner. Inhibition of direct cell-to-cell infection did not affect the formation of virological synapses or the subsequent cell-to-cell transfer of HIV-1. During both cell-free and cell-to-cell CD4 ؉ T lymphocyte infection, purinergic antagonists blocked infection at the level of viral membrane fusion. During cell-to-cell transmission, we observed CXCR4 colocalization with the newly internalized virus particles within target lymphocytes and found that the purinergic antagonists did not impair the recruitment of the coreceptor CXCR4 to the site of Gag internalization in the target cell. In a screen of a library of purinergic antagonists, we found that the most potent inhibitors of HIV-1 fusion were those that target P2X receptors, while P2Y-selective receptor antagonists or adenosine receptor antagonists were ineffective. Our results suggest that P2X receptors may provide a therapeutic target and that purinergic antagonists may have potent activity against viral infection of CD4 ؉ T lymphocytes by both cell-free and cell-to-cell transmission. IMPORTANCEThis study identifies purinergic antagonists to be potent inhibitors of HIV-1 cell-free and cell-to-cell-mediated infection and provides a stepwise determination of when these compounds inhibit HIV-1 infection. These data provide a rationale for the development of novel antiretroviral therapies that have a dual role in both direct antiviral activity and the reduction of HIV-associated inflammation. Purinergic antagonists are shown here to have equivalent efficacy in inhibiting HIV infection via cell-free and cell-to-cell infection, and it is shown that purinergic receptors could provide an attractive therapeutic anti-HIV target that might avoid resistance by targeting a host signaling pathway that potently regulates HIV infection. The high-throughput screen of HIV-1 fusion inhibitors further defines P2X-selective compounds among the purinergic compounds as being the most potent HIV entry inhibitors. Clinical studies on these drugs for other inflammatory indications suggest that they are safe, and thus, if developed for use as anti-HIV agents, they could reduce both HIV replication and HIV-related inflammation.

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“…P2X3, P2X2/3, P2X4, and P2X7 receptors have received a lot of recent attention as potential targets to treat a variety of conditions that include chronic pain and arthritis [44]. Clinically the P2X7 receptor antagonists CE-224535 and AZD9056 have not demonstrated efficacy in rheumatoid arthritis and it is unknown whether they may be useful in pain indications [45,46]. P2X3 receptor expression changes in animal pain models of P2X3 knock-out mice have shown the development of reduced mechanical allodynia [47] and neuronal P2X3 receptor activation predisposing afferent neurons to inflammatory hyperalgesia [48].…”

Section: Introductionmentioning

confidence: 99%

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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Introduction: Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain.Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC. They review repurposed and new pharmacological treatments. Several meta-analyses were performed to compare the efficacy of treatments where possible.Expert opinion: Repurposed pain medications such as gabapentin and pregabalin reduce the frequency of cough and improve quality of life. Along with speech pathology, they are important and alternate treatments for refractory CC. However, more treatments are needed and the P2X3 ion channel receptor antagonists show the most promise. With a better understanding of neuronal activation and sensitisation and their signal processing in the brain, improved animal models of cough, and the use of validated cough measurement tools, more effective treatments will develop.

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Efficacy and Safety of CE-224,535, an Antagonist of P2X₇Receptor, in Treatment of Patients with Rheumatoid Arthritis Inadequately Controlled by Methotrexate

Abstract: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.

Cited by 211 publications

References 31 publications

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

An update and systematic review on drug therapies for the treatment of refractory chronic cough

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Efficacy and Safety of CE-224,535, an Antagonist of P2X7Receptor, in Treatment of Patients with Rheumatoid Arthritis Inadequately Controlled by Methotrexate

Abstract: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.

Cited by 211 publications

References 31 publications

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

An update and systematic review on drug therapies for the treatment of refractory chronic cough

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Efficacy and Safety of CE-224,535, an Antagonist of P2X₇Receptor, in Treatment of Patients with Rheumatoid Arthritis Inadequately Controlled by Methotrexate