ChemMedChem 2020 Dec 15;1524:2530-2543. doi: 10.1002/cmdc.202000303.

Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists.

???displayArticle.abstract???
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)methyl-benzamides 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 inhibitory 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 inhibitors 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 IC 50 value of 0.39 μΜ.

???displayArticle.pubmedLink??? 32964578
???displayArticle.link??? ChemMedChem
???displayArticle.grants??? [+]

Species referenced: Xenopus laevis
Genes referenced: p2rx7