Design, Synthesis and Anti-Inflammation Evaluation of -Acyl Tryptophan Derivatives as Promising P2YR Antagonists Against Lipopolysaccharide-Induced Acute Lung Injury.

PURPOSE

The P2Y receptor (P2YR) is closely associated with several inflammatory diseases in humans. Although several P2YR antagonists have been reported to date, few have been successfully developed as therapeutic drugs, and none have entered clinical trials. We aimed to obtain P2YR antagonists with high antagonistic activity and druggability for further investigation into anti-inflammatory drugs.

METHODS

Three series of novel P2YR 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.

RESULTS

We designed a series of -acyl tryptophan derivatives as novel and potent P2YR antagonists based on the hit compound . Among them, compound with an IC value of 1.2 nM, was a better antagonist than with an IC 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 P2YR is highly expressed in macrophages of ALI lung tissue. II-3, as a P2YR 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 P2YR as a therapeutic target.

CONCLUSION

Compound with potent P2YR antagonistic activity, may be a promising candidate for further investigation as an anti-inflammatory drug.