Discovery of a series of novel 3-sulfonamido benzoic acid derivatives as promising P2Y14R antagonists for acute lung injury

Abstract

The P2Y₁₄ receptor (P2Y₁₄R) has been identified as a potential target for various inflammatory diseases, particularly acute lung injury (ALI). However, very few P2Y₁₄R antagonists have been reported so far, especially those with innovative scaffolds. And none have entered clinical trials due to the shortcomings of low antagonistic activity and poor druggability. Herein, we designed, synthesized and evaluated a series of 3-sulfonamido benzoic acid derivatives as P2Y₁₄R antagonists with novel scaffolds based on PPTN, which is considered to be the most potent P2Y₁₄R antagonist. Among them, compound 25l (IC₅₀ = 5.6 ± 0.3 nM) emerged as the most potent P2Y₁₄R antagonist, exhibiting not only significantly better antagonistic activity compared to the rest but also superior binding affinity to P2Y₁₄R over PPTN. Moreover, the solubility and pharmacokinetic properties of compound 25l were proven to be better than those of PPTN. The anti-inflammatory effect of compound 25l was investigated using an LPS-induced mouse ALI model. The results showed that compound 25l significantly reduced the inflammatory response in lung tissues and the levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) induced by LPS. Therefore, compound 25l, with its potent P2Y₁₄R antagonistic activity and favorable druggability, is a promising candidate for further investigation as an anti-inflammatory drug.