BAY 61-3606 is an Orally Active and Highly Selective SYK Inhibitor for Inflammatory Diseases

Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase. Syk plays an important role in allergic diseases and inflammation. Thus, Syk is an attractive target for therapeutic kinase inhibitors. This effects ameliorates symptoms and consequences of acute and chronic inflammation. Syk participates that have made this kinase such a compelling drug target. In this study, NORIYUKI YAMAMOTO, et al identify an orally available Syk kinase inhibitor BAY 61-3606 from a series of imidazopyrimidine analogs. Especially, BAY 61-3606 inhibits kinase activity of Syk in a concentration-dependent manner with an IC50 value of 10 nM.

BAY 61-3606 is a highly selective inhibitor of Syk kinase. BAY 61-3606 does not inhibit other selected tyrosine kinases, Lyn, Fyn, Src, Itk, and Btk in concentrations up to 4.7μM.

Moreover, BAY 61-3606 inhibits not only degranulation (IC50 values between 5 and 46 nM) but also lipid mediator and cytokine synthesis in mast cells. BAY 61-3606 is highly efficacious in basophils obtained from healthy human subjects (IC50=10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC50= 8.1 nM). In a manner similar to its effect on the degranulation of RBL-2H3 cells and rat peritoneal mast cells, BAY 61-3606 inhibits FcεRI-mediated histamine and tryptase release from HCMCs with IC50 values of 5.1 and 5.5 nM, respectively. BAY 61-3606 also inhibits the degranulation of human freshly isolated basophils. BAY 61-3606 also inhibits B cell receptor (BCR)-mediated signaling.

All in all, BAY 61-3606 is a potent (Ki = 7.5 nM) and selective Syk kinase inhibitor for many immune diseases.

Yamamoto N, et al. The orally available spleen tyrosine kinase inhibitor 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]nicotinamide dihydrochloride (BAY 61-3606) blocks antigen-induced airway inflammation in rodents. J Pharmacol Exp Ther. 2003 Sep;306(3):1174-81.