Han Bingqian, Ma Shiyu, Liu Wenjin, Wang Yuyang, Wang Mingzhu, Li Yuanzhe, Song Chuanjun, Yao Yongfang, Sun Moran, Duan Yongtao
Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
Drug Des Devel Ther. 2025 Aug 20;19:7215-7245. doi: 10.2147/DDDT.S497291. eCollection 2025.
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.
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.
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.
Compound with potent P2YR antagonistic activity, may be a promising candidate for further investigation as an anti-inflammatory drug.
P2Y受体（P2YR）与人类的多种炎症性疾病密切相关。尽管迄今为止已报道了几种P2YR拮抗剂，但很少有成功开发为治疗药物的，且无一进入临床试验。我们旨在获得具有高拮抗活性和可成药性质的P2YR拮抗剂，以进一步研究抗炎药物。
筛选了三个系列的新型P2YR拮抗剂。通过细胞色素P450抑制试验、人醚 - 去极化相关基因（hERG）通道抑制试验以及药代动力学实验评估了最有前景化合物的可成药性质。在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠模型中评估了先导化合物的体内疗效。
我们基于活性化合物设计了一系列新型强效P2YR拮抗剂——酰基色氨酸衍生物。其中，IC值为1.2 nM的化合物 比IC值为2.0 nM的 是更好的拮抗剂。通过结构修饰，消除了两性离子特性，与PPTN相比，溶解度和口服生物利用度显著提高。我们已证实P2YR在ALI肺组织的巨噬细胞中高表达。II - 3作为P2YR拮抗剂，可通过抑制NLRP3炎性小体途径的激活和减少炎症因子的释放来减轻ALI的病理进程，从而为P2YR作为治疗靶点提供了直接证据。
具有强效P2YR拮抗活性的化合物 可能是一种有前景的抗炎药物进一步研究候选物。
