Design, Synthesis and Anti-Inflammation Evaluation of N-Acyl Tryptophan Derivatives as Promising P2Y₁₄R Antagonists...

The P2Y₁₄ receptor (P2Y₁₄R) is closely associated with several inflammatory diseases in humans. Although several P2Y₁₄R antagonists have been reported to date, few have been successfully developed as therapeutic drugs, and none have entered clinical trials. We aimed to obtain P2Y₁₄R antagonists with high antagonistic activity and druggability for further investigation into anti-inflammatory drugs.

Three series of novel P2Y₁₄R antagonists were screened. The druggability of the most promising compounds was evaluated through assays for the inhibition of cytochrome P450 and hERG (human Ether-à-go-go-Related Gene) channels, as well as pharmacokinetic experiments. The in vivo efficacy of the lead compound was assessed in a Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model.

We designed a series of N-acyl tryptophan derivatives as novel and potent P2Y₁₄R antagonists based on the hit compound 7. Among them, compound II-3 with an IC₅₀ value of 1.2 nM, was a better antagonist than PPTN with an IC₅₀ value of 2.0 nM. Through structural modification, the zwitterionic character was eliminated, resulting in significantly improved solubility and oral bioavailability compared to PPTN. We have confirmed that P2Y₁₄R is highly expressed in macrophages of ALI lung tissue. II-3, as a P2Y₁₄R antagonist, can alleviate the pathological progression of ALI by inhibiting the activation of the NLRP3 inflammasome pathway and reducing the release of inflammatory factors, thus providing direct evidence for P2Y₁₄R as a therapeutic target.

Compound II-3 with potent P2Y₁₄R antagonistic activity, may be a promising candidate for further investigation as an anti-inflammatory drug.