Discovery of a Series of 5-Amide-1-pyrazole-3-carboxyl Derivatives as Potent P2YR Antagonists with Anti-Inflammatory Characters.

UDPG/P2YR 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 P2YR 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 (1-(4-fluorobenzyl)-5-(4-methylbenzamido)-1-pyrazole-3-carboxylic acid, P2YR IC = 1.93 nM) showed strong binding ability to P2YR, high selectivity, notably improved solubility, and more favorable pharmacokinetic profiles. Moreover, compound possessed extremely low cytotoxicity and anti-inflammatory effect . In an acute peritonitis model, compound could effectively reduce the levels of inflammatory factor IL-6, IL-1β, and TNF-α of mice induced by LPS. Compound , with potent and efficacy and favorable druggability, can be a promising candidate for further research.