Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3-<i>a</i>]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain

Chrovian, Christa C.; Soyode-Johnson, Akinola; Ao, Hong; Bacani, Genesis M.; Carruthers, Nicholas I.; Lord, Brian; Nguyen, Leslie; Rech, Jason C.; Wang, Qi; Bhattacharya, Anindya; Letavic, Michael A.

doi:10.1021/acschemneuro.5b00303

Cited by 23 publications

(17 citation statements)

References 23 publications

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“…Although first clinical trials with P2X7R antagonists have not proven their efficacy in systemic inflammatory disorders62, recent trials proved to be more promising in terms of efficacy and all those compounds, which entered to clinical trials displayed a beneficial risk profile63. Moreover, in the past years various classes of small molecule, drug-like P2X7R inhibitors have been developed, which readily enter the brain and display high degree of target engagement in the CNS6465. Although further studies should elucidate the role of P2X7R in cortical development and its contribution to schizophrenia endophenotype, our findings points to its role as a potential target in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

The role of P2X7 receptors in a rodent PCP-induced schizophrenia model

Koványi

Csölle

Calovi

et al. 2016

Sci Rep

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P2X7 receptors (P2X7Rs) are ligand-gated ion channels sensitive to extracellular ATP. Here we examined for the first time the role of P2X7R in an animal model of schizophrenia. Using the PCP induced schizophrenia model we show that both genetic deletion and pharmacological inhibition of P2X7Rs alleviate schizophrenia-like behavioral alterations. In P2rx7+/+ mice, PCP induced hyperlocomotion, stereotype behavior, ataxia and social withdrawal. In P2X7 receptor deficient mice (P2rx7−/−), the social interactions were increased, whereas the PCP induced hyperlocomotion and stereotype behavior were alleviated. The selective P2X7 receptor antagonist JNJ-47965567 partly replicated the effect of gene deficiency on PCP-induced behavioral changes and counteracted PCP-induced social withdrawal. We also show that PCP treatment upregulates and increases the functional responsiveness of P2X7Rs in the prefrontal cortex of young adult animals. The amplitude of NMDA evoked currents recorded from layer V pyramidal neurons of cortical slices were slightly decreased by both genetic deletion of P2rx7 and by JNJ-47965567. PCP induced alterations in mRNA expression encoding schizophrenia-related genes, such as NR2A, NR2B, neuregulin 1, NR1 and GABA α1 subunit were absent in the PFC of young adult P2rx7−/− animals. Our findings point to P2X7R as a potential therapeutic target in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

The role of P2X7 receptors in a rodent PCP-induced schizophrenia model

Koványi

Csölle

Calovi

et al. 2016

Sci Rep

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“…antagonists, leading to identification of JNJ compound 25 and compound 26 (Chrovian et al, 2016). In a Ca 2+ influx assay, compound 25 has IC50 values of 8.7 nM and 42 nM at the human and rat P2X7 receptors, respectively, and compound 26 has IC50 values of 8.8 nM and 82 nM at the human and rat P2X7 receptors, respectively.…”

Section: Janssen Compoundsmentioning

confidence: 99%

ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

Wei

Mortadza

Yan

et al. 2018

Neuroscience & Biobehavioral Reviews

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Mood disorders are a group of psychiatric conditions that represent leading global disease burdens. Increasing evidence from clinical and preclinical studies supports that innate immune system dysfunction plays an important part in the pathophysiology of mood disorders. P2X7 receptor, belonging to the ligand-gated ion channel P2X subfamily of purinergic P2 receptors for extracellular ATP, is highly expressed in immune cells including microglia in the central nervous system (CNS) and has a vital role in mediating innate immune response. The P2X7 receptor is also important in neuron-glia signalling in the CNS. The gene encoding human P2X7 receptor is located in a locus of susceptibility to mood disorders. In this review, we will discuss the recent progress in understanding the role of the P2X7 receptor in the pathogenesis and development of mood disorders and in discovering CNS-penetrable P2X7 antagonists for potential uses in in vivo imaging to monitor brain inflammation and antidepressant therapeutics.

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“…At this stage we selected the 4 best compounds across the respective classes ( i.e . the P2X7 inhibitor compound 26 from 19 , MCC950, NBC19, and VX-765; dose responses to ATP and nigericin shown in Fig. 3a and b respectively).…”

Section: Resultsmentioning

confidence: 99%

“…The best inhibitor from the diarylsulfonylurea series was again MCC950 with an IC 50 of 60 nM against ATP-induced IL-1β release (Table 3 ). The P2X7 antagonists had no effect against nigericin-induced IL-1β release but were effective against ATP with AZD9056 and compound 26 (from 19 ) both inhibiting ATP-induced IL-1β release with an IC 50 of 30 nM (Table 3 ). NBC19 was again the most effective of the NBC series with an IC 50 of 850 nM against ATP-induced IL-1β release (Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…The aim of this research was to take a selection of what we considered to be the most promising lead compounds from the literature. We focussed our study on known and potent molecules for defined points in the pathway which included antagonists of the P2X7 receptor (CE-224,535 17 , AZD9056 18 , and two 5,6-dihydro-[1,2,4]triazolo[4,3-a]-pyrazine P2X7 antagonists (compounds 25 and 26 from 19 ), the diarylsulfonylurea series (glyburide through to the cytokine release inhibiting drugs (CRIDs), including MCC950 20 – 22 ), the caspase-1 inhibitor belnacasan (VX-765) 23 , and compare these to several analogues of the recently described Novel Boron Compound (NBC) inflammasome inhibitor series of boron-containing inhibitors 24 (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

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Development of a characterised tool kit for the interrogation of NLRP3 inflammasome-dependent responses

Redondo‐Castro

Faust

Fox

et al. 2018

Sci Rep

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Inflammation is an established contributor to disease and the NLRP3 inflammasome is emerging as a potential therapeutic target. A number of small molecule inhibitors of the NLRP3 pathway have been described. Here we analysed the most promising of these inhibitor classes side by side to assess relative potency and selectivity for their respective putative targets. Assessed using ASC inflammasome-speck formation, and release of IL-1β, in both human monocyte/macrophage THP1 cells and in primary mouse microglia, we compared the relative potency and selectivity of P2X7 inhibitors, inflammasome inhibitors (diarylsulfonylurea vs. the NBC series), and caspase-1 inhibitors. In doing so we are now able to provide a well characterised small molecule tool kit for interrogating and validating inflammasome-dependent responses with a range of nanomolar potency inhibitors against established points in the inflammasome pathway.

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Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain

Cited by 23 publications

References 23 publications

The role of P2X7 receptors in a rodent PCP-induced schizophrenia model

The role of P2X7 receptors in a rodent PCP-induced schizophrenia model

ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

Development of a characterised tool kit for the interrogation of NLRP3 inflammasome-dependent responses

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