Design, Synthesis, andin vitroEvaluation of P2X7 Antagonists

T. Pournara, Dimitra; Durner, Anna; Kritsi, Eftichia; Papakostas, Alexios; Zoumpoulakis, Panagiotis; Nicke, Annette und Koufaki, Maria (2020): Design, Synthesis, andin vitroEvaluation of P2X7 Antagonists. In: Chemmedchem, Bd. 15, Nr. 24: S. 2530-2543

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)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, usingXenopus laevisoocytes 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 IC(50)value of 0.39 mu M.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1860-7179
• Sprache: Englisch