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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-alpha/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 muM) and mouse bone marrow-derived mast cells (IC50 = 2.03 muM) and significantly decreased the secretion of inflammatory cytokines. Thus, Syk/PDGFR-alpha/c-Kit triple inhibitor 13 represented a promising lead compound for the treatment of RA.
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