Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y14R Antagonists with Anti-Inflammatory Characters,Journal of Medicinal Chemistry

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Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y14R Antagonists with Anti-Inflammatory Characters
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-17 , DOI: 10.1021/acs.jmedchem.2c01632
Yu-Hang Wang _{1,

2} , Meng-Ze Zhou _{1,

3} , Tao Ye _{1,

4} , Ping-Ping Wang _{1,

2} , Ran Lu _{1,

2} , Yi-Lin Wang _{1,

3} , Chun-Xiao Liu _{1,

3} , Wen Xiao _{1,

2} , Jia-Yi Li _{1,

2} , Zi-Bo Meng _{1,

2} , Li-Li Xu _{1,

2,

4} , Qing-Hua Hu _{1,

3} , Cheng Jiang _{1,

2}

Affiliation

UDPG/P2Y₁₄R 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 P2Y₁₄R 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)-1H-pyrazole-3-carboxylic acid, P2Y₁₄R IC₅₀ = 1.93 nM) showed strong binding ability to P2Y₁₄R, 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.

中文翻译：

发现一系列 5-Amide-1H-pyrazole-3-carboxyl 衍生物作为具有抗炎特性的强效 P2Y14R 拮抗剂

UDPG/P2Y ₁₄ R信号通路被认为是先天性免疫系统疾病的潜在治疗靶点。基于支架跳跃策略，设计并合成了一系列吡唑类似物作为新型 P2Y ₁₄ R 拮抗剂，具有改进的物理化学性质以及潜在的抗炎活性。此外，我们设计并合成了一种基于高选择性和强效 PPTN 的荧光探针，以研究合成化合物的亲和力。优化后的化合物16 (1-(4-fluorobenzyl)-5-(4-methylbenzamido)-1 H -pyrazole-3-carboxylic acid, P2Y ₁₄ R IC _{50 = 1.93 nM) 显示出对 P2Y}₁₄的强结合能力R，高选择性，显着改善溶解度，更有利的药代动力学特征。此外，化合物16在体外具有极低的细胞毒性和抗炎作用。在急性腹膜炎模型中，化合物16可有效降低LPS诱导的小鼠炎症因子IL-6、IL-1β和TNF-α水平。化合物16具有强大的体外和体内功效和良好的成药性，可以成为进一步研究的有前途的候选者。

更新日期：2022-11-17

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