From lead to clinic: A review of the structural design of P2X7R antagonists

P2X7R, which is a member of the purinergic P2 receptor family, is widely expressed in many immune cells, such as macrophages, lymphocytes, monocytes, and neutrophils. P2X7R is upregulated in response to proinflammatory stimulation, which is closely related to a variety of inflammatory diseases. The inhibition of P2X7 receptors has resulted in the elimination or reduction of symptoms in animal models of arthritis, depression, neuropathic pain, multiple sclerosis, and Alzheimer's disease. Therefore, the development of P2X7R antagonists is of great significance for the treatment of various inflammatory diseases. This review classifies the reported P2X7R antagonists according to their different cores, focuses on the structure-activity relationship (SAR) of the compounds, and analyzes some common substituents and strategies in the design of lead compounds, with the hope of providing valuable information for the development of new and efficient P2X7R antagonists.