Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists

The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan‐1‐yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand‐based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two‐electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl‐cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2‐chloro‐N‐[1‐(3‐(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μM.