Design, synthesis and anti-inflammatory evaluation of 3-amide benzoic acid derivatives as novel P2Y14 receptor antagonists

Abstract

The P2Y₁₄ receptor (P2Y₁₄R) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2Y₁₄R antagonists. The most potent antagonist, 16c, showed comparable activity (IC₅₀ = 1.77 nM) to PPTN, the most potent P2Y₁₄R antagonist reported. Compound 16c demonstrated dramatically improved aqueous solubility and excellent metabolic stability in rat and human microsomes. Investigation of the anti-inflammatory effect of 16c was performed in MSU treated THP-1 cells by flow cytometry, Western Blot and immunofluorescence labeling technology, which exhibited that 16c might be a promising candidate for further research.

Keywords: 3-Amide benzoic acid derivatives; Antagonist; Anti-inflammation; G protein-coupled receptor; P2Y(14) receptor.