Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation

The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several antagonists have been developed, though none them reached clinical trials for this indication. In work, we designed and synthesized novel blood–brain barrier (BBB)-permeable derivatives as potential antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested YO-PRO-1 uptake assays intracellular calcium dynamics a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings Xenopus laevis oocytes, interleukin 1β release mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured certain blockade, being compound 6 (2-(6-chloro-9H-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, most potent, selective, BBB-permeable antagonist. Compound can be considered first non-nucleotide hit future drug optimizations.