Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists

Rudolph, Dale A.; Alcázar, Jesús; Ameriks, Michael K.; Antón, Ana B.; Ao, Hong; Bonaventure, Pascal; Carruthers, Nicholas I.; Chrovian, Christa C.; Angelis, Meri De; Lord, Brian; Rech, Jason C.; Wang, Qi; Bhattacharya, Anindya; Andrés, Juvenal; Letavic, Michael A.

doi:10.1016/j.bmcl.2015.06.004

Cited by 30 publications

(16 citation statements)

References 12 publications

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“…These structures indicate that the P2X7 receptor tolerates very bulky residues, like cycloheptyl, adamantyl and related ring systems. Several other P2X7 antagonists that penetrate well into the brain have recently been described, including GSK1482160 ( 146 ), which has been prepared in 11 C-labeled form to provide a ligand for positron emission tomography (PET) studies (Gao et al, 2015), JNJ-47865567 ( 147 ) (Letavic et al, 2013; Bhattacharya et al, 2013), JNJ-42253432 ( 148 ) (Lord et al, 2014) and the triazolopyrazinylmethanone 149 (Rudolph et al, 2015). A novel, useful 3H-labeled antagonist radioligand, [ 3 H]JNJ-54232334 ( 150 ) has been reported (Lord et al, 2015).…”

Section: P2xr Modulatorsmentioning

confidence: 99%

Medicinal chemistry of adenosine, P2Y and P2X receptors

2016

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Pharmacological tool compounds are now available to define action at the adenosine (ARs), P2Y and P2X receptors. We present a selection of the most commonly used agents to study purines in the nervous system. Some of these compounds, including A1 and A3 AR agonists, P2Y1R and P2Y12R antagonists, and P2X3, P2X4 and P2X7 antagonists, are potentially of clinical use in treatment of disorders of the nervous system, such as chronic pain, neurodegeneration and brain injury. Agonists of the A2AAR and P2Y2R are already used clinically, P2Y12R antagonists are widely used antithrombotics and an antagonist of the A2AAR is approved in Japan for treating Parkinson’s disease. The selectivity defined for some of the previously introduced compounds has been revised with updated pharmacological characterization, for example, various AR agonists and antagonists were deemed A1AR or A3AR selective based on human data, but species differences indicated a reduction in selectivity ratios in other species. Also, many of the P2R ligands still lack bioavailability due to charged groups or hydrolytic (either enzymatic or chemical) instability. X-ray crystallographic structures of AR and P2YRs have shifted the mode of ligand discovery to structure-based approaches rather than previous empirical approaches. The X-ray structures can be utilized either for in silico screening of chemically diverse libraries for the discovery of novel ligands or for enhancement of the properties of known ligands by chemical modification. Although X-ray structures of the zebrafish P2X4R have been reported, there is scant structural information about ligand recognition in these trimeric ion channels. In summary, there are definitive, selective agonists and antagonists for all of the ARs and some of the P2YRs; while the pharmacochemistry of P2XRs is still in nascent stages. The therapeutic potential of selectively modulating these receptors is continuing to gain interest in such fields as cancer, inflammation, pain, diabetes, ischemic protection and many other conditions. Reported potencies refer to the human receptors unless otherwise noted. Additional affinity data can be found in recent review papers (Müller and Jacobson, 2011; Jacobson et al., 2015; Coddou et al., 2011a).

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Section: P2xr Modulatorsmentioning

confidence: 99%

Medicinal chemistry of adenosine, P2Y and P2X receptors

2016

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“…9,195 Some P2X 7 receptor antagonists were specifically developed to study disorders of the CNS. These are the brain penetrant benzamides GSK1482160, 196 JNJ-42253432, 197 JNJ-47965567, 198 triazoles JNJ-54232334 and JNJ-54140515, 199 JNJ-54166060, 200 JNJ-54173717, 201 JNJ-54175446, 202 and JNJ-55308942. 203 These molecules have demonstrated P2X 7 receptor antagonist activities in rodent and human.…”

Section: P2x 7 Receptor and Functions In The Cnsmentioning

confidence: 99%

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

Zarrinmayeh

Territo

2020

Mol Imaging

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Purinergic receptors play important roles in central nervous system (CNS). These receptors are involved in cellular neuroinflammatory responses that regulate functions of neurons, microglial and astrocytes. Based on their endogenous ligands, purinergic receptors are classified into P1 or adenosine, P2X and P2Y receptors. During brain injury or under pathological conditions, rapid diffusion of extracellular adenosine triphosphate (ATP) or uridine triphosphate (UTP) from the damaged cells, promote microglial activation that result in the changes in expression of several of these receptors in the brain. Imaging of the purinergic receptors with selective Positron Emission Tomography (PET) radioligands has advanced our understanding of the functional roles of some of these receptors in healthy and diseased brains. In this review, we have accumulated a list of currently available PET radioligands of the purinergic receptors that are used to elucidate the receptor functions and participations in CNS disorders. We have also reviewed receptors lacking radiotracer, laying the foundation for future discoveries of novel PET radioligands to reveal these receptors roles in CNS disorders.

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“…JNJ-54173717, which has nanomolar affinity for rat P2X 7 R and hP2X 7 R, 219,220 was radiolabeled with 11 C and evaluated in vivo in rats and NHPs. 221 Biodistribution studies conducted in normal rats demonstrated that [ 11 C]JNJ-54173717 readily crossed the BBB and was cleared from plasma mainly via the hepatobiliary pathway.…”

Section: Purinergic Receptors-p2x 7 and P2y 12mentioning

confidence: 99%

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

et al. 2018

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The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

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Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists

Cited by 30 publications

References 12 publications

Medicinal chemistry of adenosine, P2Y and P2X receptors

Medicinal chemistry of adenosine, P2Y and P2X receptors

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

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