Due to the complex biological pathways involved in rheumatoid arthritis, discovery of multi-targeting small molecules provides an effective strategy to achieve better efficacy and lower toxicity. Herein the first Syk/PDGFR-α/c-Kit inhibitors were designed and evaluated. Dihydrofuropyrimidine derivative 13 showed potent inhibitory activity against the three targets. Importantly, compound 13 exhibited good cellular efficacy against fibroblast-like synoviocytes (IC₅₀ = 3.21 μM) and mouse bone marrow-derived mast cells (IC₅₀ = 2.03 μM) and significantly decreased the secretion of inflammatory cytokines. Thus, Syk/PDGFR-α/c-Kit triple inhibitor 13 represented a promising lead compound for the treatment of RA.

由于类风湿关节炎涉及复杂的生物途径，发现多靶点小分子提供了一种有效的策略，以实现更好的疗效和更低的毒性。本文设计并评估了首批Syk /PDGFR-α/ c-Kit抑制剂。二氢呋喃基嘧啶衍生物13显示出对三个靶标的有效抑制活性。重要的是，化合物13对成纤维细胞样滑膜细胞（IC ₅₀  = 3.21μM）和小鼠骨髓来源的肥大细胞（IC ₅₀  = 2.03μM）表现出良好的细胞效力，并显着降低了炎性细胞因子的分泌。因此，Syk /PDGFR-α/ c-Kit三联抑制剂13代表了有前途的铅化合物治疗RA。