Spleen tyrosine kinase (Syk) is broadly involved in regulating leukocyte immune function, principally by facilitating cellular activation in response to receptor engagement of antigen or of immune complex. Coffey et al. report on the discovery and characterization of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R, 2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a novel, highly specific and potent orally available small-molecule inhibitor of Syk; they test the hypothesis that specific pharmacological inhibition of Syk kinase activity is sufficient to modulate leukocyte immune function and ameliorate inflammation in vivo. P505-15 potently and specifically inhibited Syk kinase activity in vitro (including whole blood assays), and ex vivo after oral dosing of P505-15, without inhibiting Syk-independent signaling. Submicromolar concentrations in blood, predicted to result in 67% inhibition of Syk, led to statistically significant anti-inflammatory effects in the mouse collagen antibody-induced arthritis (CAIA) and the rat collagen-induced arthritis (CIA) models. Syk kinase inhibition by P505-15 mimics the immunomodulatory phenotype of Syk knockout observed in other rodent models of rheumatoid arthritis. These data suggest that the specific inhibition of Syk may be a sufficient and safe strategy to control immune function in inflammatory diseases. P505-15 is currently in clinical development for the treatment of inflammatory diseases.

See article at J Pharmacol Exp Ther 2012, 340:350–359.

• Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics