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ACS Medicinal Chemistry Letters
 
ACS Med Chem Lett. 2016 April 14; 7(4): 348–350.
Published online 2016 March 4. doi:  10.1021/acsmedchemlett.6b00083
PMCID: PMC4834659

Promising Therapeutic Potential of P2X7 Modulators

Patent Application Title:P2X7 Modulators
Patent Application Number:US 20160024082AlPublication date:Jan 28, 2016
Inventors:Alcazar Vaca, M. J.; Andres Gil, J. I.; Letavic, M. A.; Rudolph, D. A.; Shireman, B. T.; Stenne, B. M.; Ziff, J. M.
Assignee Company:Janssen Pharmaceutica NV, Beerse (BE)
Disease Area:Resistant depression, diseases of the autoimmune and inflammatory system, diseases involved with or without neuro-inflammation of the CNS, and diseases of the cardiovascular, metabolic, gastrointestinal, and urogenital systemsBiological Target:ATP-gated P2X7 receptor channel
Summary:The invention in this patent application is related to 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives represented generally by formula (I). These compounds possess P2X7 modulating activities and may be useful for the treatment of diseases associated with P2X7 receptor activities including but not limited to diseases of the autoimmune and inflammatory system, diseases involved with or without neuro-inflammation of the CNS, and diseases of the cardiovascular, metabolic, gastrointestinal, and urogenital systems.
The inventors mentioned in the claims a long list of specific disorders and diseases that may potentially be treated with the compounds of the invention including rheumatoid arthritis, osteoarthritis, psoriasis, inflammatory pain, spontaneous pain, opioid induced pain, diabetic neuropathy, resistant depression, bipolar disorder, anxious depression, sleep disorders, multiple sclerosis, epileptic seizures, Parkinson’s disease, schizophrenia, Alzheimer’s disease, Huntington’s disease, and many more. However, they claimed the treatment of resistant depression separately.
Adenosine triphosphate (ATP) is an important extracellular signaling molecule that functions through a complex purinergic signaling network. This network contains a number of membrane receptors and ectoenzymes that include the P2X7 receptor. The P2X7 receptor is one of seven members of the P2X family of trimeric ligand-gated cation channels, named P2X1–7. The P2X7 receptor is found on a variety of cell types, particularly those involved in the inflammatory and/or immune process, specifically, macrophages and monocytes in the periphery and predominantly in glial cells (microglia and astrocytes) of the CNS. P2X7 receptors are also located on antigen-presenting cells (keratinocytes, salivary acinar cells (parotid cells), hepatocytes, erythrocytes, erythroleukemic cells, monocytes, fibroblasts, bone marrow cells, neurons, and renal mesangial cells. Activation of P2X7 receptors is responsible for a number of downstream events such as the release of proinflammatory cytokines IL-lβ and IL-18, giant cell formation (macrophages/microglial cells), degranulation (mast cells) and l-selectin shedding (lymphocytes), and cell death and proliferation. The P2X7 receptor plays several important roles in various inflammatory, immune, neurologic, and musculoskeletal disorders. Studies have shown that P2X7 knock out mice were protected from the development of both adjuvant-induced inflammatory pain and partial nerve ligation induced neuropathic pain. This observation has underscored an important role of the P2X7 receptor in the development and maintenance of pain. It was also observed that P2X7 knock out mice exhibit an antidepressant phenotype. Studies have shown a link between precipitation of mood disorders and the release of the pro-inflammatory cytokine IL-lβ resulting from activation of the P2X7 receptor. In addition, the murine models of Alzheimer’s disease showed that P2X7 is upregulated around amyloid plaques, thus indicating a role of the P2X7 receptor in the pathology of this disease.
The foregoing studies and observations suggest that P2X7 receptor is a viable therapeutic target for the treatment of inflammatory diseases and potentially other diseases. The identification of P2X7 antagonists that can modulate the P2X7 receptor function such as the compounds of this invention may lead to the development of new useful therapeutic agents.
Important Compound Classes:
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Formula (I)
Key Structures:The inventors described the synthesis of 147 compounds as examples of formula (I) including the following:
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Biological Assay:The inventors described the following assays to test the compounds of the invention:
  • • P2X7 Antagonism in Human Peripheral Blood Mononuclear Cells (PBMCs) and Human Whole Blood
  • • P2X7 Antagonism in Recombinant Human P2X7 Cells or Recombinant Rat P2X7 Cells: (a) Ca2+ Flux and (b) Radioligand Binding
Biological Data:The following table contains the testing data obtained from the above representative examples:
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PBMC = Peripheral Blood Mononuclear Cells; FLIPR = Fluorometric Imaging Plate Reader
Recent Review Articles:1. Muller C. E.. Curr. Med. Chem. 2015, 22 (7), 929–941. [PubMed]
 2. Baudelet D.; Lipka E.; Millet R.; Ghinet A.Curr. Med. Chem. 2015, 22 (6), 713–729. [PubMed]
 3. Coddou C.; Stojilkovic S.S.; Huidobro-Toro J.P.Rev. Neurosci. 2011, 22 (3), 335–354. [PubMed]

Notes

The authors declare no competing financial interest.


Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society