Synthesis and in vitro activity of N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine P2X7 antagonists

Synthesis and biological evaluation of a novel class of substituted N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X7 antagonists. These compounds were assayed for activity at both the human and rat P2X7 receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents. Ortho-substitution on the benzyl group provided the greatest potency. The ortho-substituted analogs showed approximately 2.5-fold greater potency at human compared to rat P2X7 receptors. Compounds 12 and 38 displayed hP2X7pIC50s >7.8 with less than 2-fold difference in potency at the rP2X7.

Graphical abstractThe synthesis and structure–activity relationship studies of P2X7 antagonists are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide