期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 23, 页码 15967-15990出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01632
关键词
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资金
- National Natural Science Foundation of China [82073685, 81773745, 81872867, 82173675]
- Open -end Funds of Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening [HY201902]
- `Qinglan Project' of Jiangsu Province
- Fundamental Research Funds for the Central Universities [2632021ZD13]
A series of novel P2Y14R antagonists were designed and synthesized with improved physicochemical properties and potential anti-inflammatory activities. Compound 16 showed strong binding ability to P2Y14R, improved solubility, and favorable pharmacokinetic profiles, as well as anti-inflammatory effects in vitro and in vivo.
UDPG/P2Y14R signaling pathway has been consid-ered 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-1 beta, and TNF-alpha 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.
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