Discovery of novel purine-based heterocyclic P2X7 receptor antagonists

Abstract The pyridine core skeleton of the previously reported dichloropyridine-based potent h P2X 7 receptor antagonist 5 (IC 50  = 13 nM in h P2X 7 -expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 9o exhibited the most potent antagonistic activity, with an IC 50 value of 176 ± 37 nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1β release in THP-1 cells stimulated with LPS/IFN-γ/BzATP (IC 50  = 120 ± 15 nM). Although 9o was less active than the previous antagonist 5 , 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse).