Design, Synthesis, And Biological Evaluation Of Novel Syk Inhibitors For Application To Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is a systemic autoimmune disease which can lead high disability and serious injury. Until now, there are no effective targeted drugs to treat RA. Spleen tyrosine kinase (Syk) is a non-receptor kinase which is involved in release of key mediators and signal transduction in a variety of cell types associated with RA. Syk is considered to be the most promising target for the treatment of RA. Our research group found one compound (A01) with potent Syk inhibitory activity through random screening. Base on the structure of A01, we designed and synthesized46heterocyclic substituted styrene-containing derivatives (A02-47), in which36derivatives (A12-A47) are characterized by novel structure. All of the derivatives were evaluated by mobility shift assay against Syk. The results indicated that27derivatives may be considered as Syk inhibitors,11derivatives showed potent Syk inhibitory activities (IC50≤2μM),16derivatives showed moderate Syk inhibitory activities (2pM<IC20≤10μM), and totally17derivatives showed better Syk inhibitory activities than the lead compound (A01). To evaluate the application to RA treatment of these Syk inhibitors, anti-proliferation activities on adjuvant arthritis fibroblast-like synoviocytes (AA FLS) in vitro of the five Syk inhibitors have been evaluated. The result indicated that3derivatives (A02, A06and All) can obviously inhibit (inhibitory rate>30%@10μM) the aberrant proliferation of AA FLS induced by TNF-a dose-dependently. It is remarkable that the effective concentrations (IC50) of A06(inhibitory rate=59.95%@10μM) and All (inhibitory rate=61.71%@10μM) are5-10μM in inhibition of the proliferation of AA FLS, which is more potent than that of phase Ⅲ candidate R788(inhibitory rate=36.13%@10μM). The activity result of All in cell assay is in good accordance to effects on the inhibition of Syk of it. This indicates that derivative All is a good lead for designing more potent Syk inhibitors for application to RA treatment. On the basis of the biological tests, we summarized the structure-activity relationship of Syk inhibitors. This work provided useful information about the further structural optimization and contributed to find novel scaffolds Syk inhibitors for treatment of RA with independent intellectual property rights.