The P2X7 receptor is a ligand-gated ion channel expressed predominantly on hematopoietic cells, including macrophages and monocytes in the periphery and microglia and astrocytes in the CNS. P2X7 is activated by high intracellular concentrations of ATP, which are present following inflammatory stimuli. The downstream effects of P2X7 activation, both in the periphery and the CNS, include the upregulation of signalling pathways involved in the release of pro-inflammatory cytokines. Various neuropsychiatric and neurodegenerative disorders are associated with neuroinflammatory cascades, which may be initiated by inflammatory cytokine signalling in the brain. Over the last decade, P2X7 antagonists have been evaluated in the clinic for their ability to attenuate rheumatoid arthritis in patients whose disease was inadequately controlled. Although these clinical trials have not been successful, to date P2X7 antagonists have not been tested for the treatment neuroinflammatory disease states associated with microglia or astrocyte activation. Herein we disclose novel P2X7 antagonists, their synthesis, SAR, and potential as orally available brain penetrant compounds for the treatment of a variety of neuroinflammatory disorders.

Synthesis, SAR, and progress toward orally available, brain penetrant P2X7R antagonists for the treatment of neuroinflammatory disorders

249th National Meeting (2015)

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