发现N替代的乙胺衍生物作为有前途的P2Y14R对手,使用基于晶体学覆盖的分子杂交
Wenjin Liu1,2, Shuqiang Mao3, Yuyang Wang1
1Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
Journal of medicinal chemistry
|June 14, 2024
概括
一种新的P2Y14受体对抗剂,化合物I-17,在痛风性关节炎模型中有效降低了炎症. 这种强大的化合物显示出作为治疗炎症疾病的治疗的希望.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 免疫学 免疫学 免疫学
背景情况:
- P2Y14受体 (P2Y14R) 在人类炎症性疾病中起作用.
- 尿素5'-二酸盐-葡萄糖是一种P2Y14R的激活剂.
研究的目的:
- 设计,合成和识别新的P2Y14R对手.
- 评估化合物I-17在治疗急性痛风性关节炎中的疗效.
主要方法:
- 分子对接和结晶学重叠研究为N替代乙胺衍生物的设计提供了信息.
- 化合物I-17被合成并以其P2Y14R对抗活性 (IC50 = 0.6 nM) 进行特征.
- 在体外和体内研究评估了I-17在单酸盐 (MSU) 诱导的急性痛风性关节炎中的抗炎作用,包括它对NLRP3/GSDMD途径的影响.
主要成果:
- 化合物I-17显示出强大的P2Y14R对抗性,具有高选择性和有利的药理动力学 (生物可用性75%).
- 在MSU诱导的急性痛风性关节炎模型中,I-17显著抑制了炎症反应.
- 通过调节NLRP3/GSDMD信号通路,I-17降低了炎症因子释放和细胞烧死.
结论:
- 化合物I-17是一种强大的,选择性的P2Y14R抗剂,已证明在体外和体内有效.
- I-17通过NLRP3 / GSDMD途径抑制炎症和热的能力使其成为急性痛风性关节炎治疗的有希望的化合物.
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