Discovery of a Series of 5-Amide-1 H -pyrazole-3-carboxyl Derivatives as Potent P2Y 14 R Antagonists with Anti-Inflammatory Characters

作者：Yuhang Wang, Mengze Zhou, Ye Tao, Pingping Wang, Ran Lu, Yilin Wang, Chunxiao Liu, Wen Xiao, Jiayi Li, Zibo Meng, Lili Xu, Qinghua Hu, Cheng Jiang · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.2c01632 · 被引用次数：18 · 研究领域：Adenosine and Purinergic Signaling、Macrophage Migration Inhibitory Factor、Synthesis and Biological Evaluation

UDPG/P2Y 14 R signaling pathway has been considered as a potential therapeutic target for innate immune system diseases. Based on the scaffold hopping strategy, a series of pyrazole analogues were designed and synthesized as novel P2Y 14 R antagonists with improved physicochemical properties, together with potential anti-inflammatory activities. Additionally, we designed and synthesized a fluorescent probe based on highly selective and potent PPTN to study the affinity of synthesized compounds. The optimized compound 16 (1-(4-fluorobenzyl)-5-(4-methylbenzamido)-1 H -pyrazole-3-carboxylic acid, P2Y 14 R IC 50 = 1.93 nM) showed strong binding ability to P2Y 14 R, high selectivity, notably improved solubility, and more favorable pharmacokinetic profiles. Moreover, compound 16 possessed extremely low cytotoxicity and anti-inflammatory effect in vitro . In an acute peritonitis model, compound 16 could effectively reduce the levels of inflammatory factor IL-6, IL-1β, and TNF-α of mice induced by LPS. Compound 16, with potent in vitro and in vivo efficacy and favorable druggability, can be a promising candidate for further research.