Discovery of novel purine-based heterocyclic P2X(7) receptor antagonists

Abstract

The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X(7) receptor antagonist 5 (IC50 = 13 nM in hP2X(7)-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 90 exhibited the most potent antagonistic activity, with an IC50 value of 176 +/- 37 nM in an ethidium bromide uptake assay. In addition, 90 significantly inhibited IL-1 beta release in THP-1 cells stimulated with LPS/IFN-gamma/BzATP (IC50 = 120 +/- 15 nM). Although 90 was less active than the previous antagonist 5, 90 exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse). (C) 2015 Elsevier Inc. All rights reserved.