Synthesis and in vitro activity of N′-cyano-4-(2-phenylacetyl)-N-o-tolylpiperazine-1-carboximidamide P2X7 antagonists

A novel series of cyanoguanidine-piperazine P2X7 antagonists was designed based upon the structure of A-740003. Structure–activity relationship (SAR) studies focused on the piperazine moiety and the right hand side substitution. Compounds were assayed for activity at human and rat P2X7 receptors and compound 29 was found to possess potent activity (IC50 = 30–60 nM) at both species.

Graphical abstractA novel series of cyanoguanidine-piperazine P2X7 antagonists was designed with compound 29 displaying potent activity (IC50 = 30–60 nM) at both rat and human P2X7.Figure optionsDownload full-size imageDownload as PowerPoint slide