The evolution of P2X7 antagonists with a focus on CNS indications

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 16; pp. 3838 - 3845
• Main Authors: Rech, Jason C., Bhattacharya, Anindya, Letavic, Michael A., Savall, Brad M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.08.2016
• Subjects: Animals; Brain penetrant; Central Nervous System Diseases - drug therapy; Central Nervous System Diseases - metabolism; Clinical Trials as Topic; Cytokines - metabolism; Half-Life; Heteroaromatic; Heterocyclic; Humans; IL-1β; Inflammation - prevention & control; Neuroinflammation; P2X7; Protein Binding; Purinergic; Purinergic P2X Receptor Antagonists - chemistry; Purinergic P2X Receptor Antagonists - pharmacokinetics; Purinergic P2X Receptor Antagonists - therapeutic use; Receptors, Purinergic P2X7 - chemistry; Receptors, Purinergic P2X7 - metabolism; Brain penetrant; P2X7; Neuroinflammation; Purinergic; Heteroaromatic; IL-1β; Heterocyclic
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.06.048

[Display omitted] The P2X7 receptor is an ATP-gated nonselective cation channel that has been linked to a number of inflammatory diseases. Activation of the P2X7 receptor by elevated levels of ATP results in the release of proinflammatory cytokines and elevated levels of these cytokines has been associated with a variety of disease states. A number of research groups in both industry and academia have explored the identification of P2X7R antagonists as therapeutic agents. Much of this early effort focused on the treatment of diseases related to peripheral inflammation and resulted in several clinical candidates, none of which were advanced to market. The emerging role of the P2X7 receptor in neuroinflammation and related diseases has resulted in a shift in medicinal chemistry efforts toward the development of centrally penetrant antagonists. This review will highlight the biology supporting the role of P2X7 in diseases related to neuroinflammation and review the recent medicinal chemistry efforts to identify centrally penetrant antagonists.