Structure–activity relationship studies of imidazo[1,2- c]pyrimidine derivatives as potent and orally effective Syk family kinases inhibitors

The conversion of 1,2,4-triazolo[4,3- c]pyrimidine to a imidazo[1,2- c]pyrimidine derivative improves in vivo efficacy of suppression of both passive cutaneous anaphylaxis (PCA) reaction and ConA-induced IL-2 production. Additionally, the inhibitory effects of the derivatives on Syk family kinase activity were assessed. Spleen tyrosine kinase (Syk) and zeta-associated protein kinase of 70 kDa (ZAP-70) are members of the Syk family and non-receptor-type protein tyrosine kinases, which play crucial roles in B- and T-cell activation. Therefore, a Syk family tyrosine kinases inhibitor would be a useful therapeutic agent for the treatment of various allergic disorders and autoimmune diseases. Previously, we reported that 1,2,4-triazolo[4,3- c]pyrimidine derivative 1 and 1,2,4-triazolo[1,5- c]pyrimidine derivative 2 showed strong inhibitory activities against Syk family kinases. These compounds also exhibited high-level suppression of IL-2 in cellular assays. However, their oral efficacies were poor in a mouse model of IL-2 production. To improve oral effectiveness, we investigated a new series of Syk family kinases inhibitors. We found that imidazo[1,2- c]pyrimidine derivatives potently inhibited the Syk family kinases. Among these agents, compound 9f not only showed strong inhibitory activities against Syk and ZAP-70 kinases in vitro, but its oral administration resulted in the in vivo suppression of both the passive cutaneous anaphylaxis reaction and Concanavalin A-induced IL-2 production in a mouse model.