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

Abstract

Spleen tyrosine kinase (Syk) tyrosine kinase plays essential roles in receptors for Fc portion of immunoglobulins and B cell receptor complex signaling in various inflammatory cells; therefore, inhibitors of Syk kinase may show potential as antiasthmatic/allergic therapeutics. We identified 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-nicotinamide dihydrochloride (BAY 61-3606), a potent (K i ϭ 7.5 nM) and selective inhibitor of Syk kinase. BAY 61-3606 inhibited not only degranulation (IC 50 values between 5 and 46 nM) but also lipid mediator and cytokine synthesis in mast cells. BAY 61-3606 was highly efficacious in basophils obtained from healthy human subjects (IC 50 ϭ 10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC 50 ϭ 8.1 nM). B cell receptor activation and receptors for Fc portion of IgG signaling in eosinophils and monocytes were also potently suppressed by BAY 61-3606. Oral administration of BAY 61-3606 to rats significantly suppressed antigen-induced passive cutaneous anaphylactic reaction, bronchoconstriction, and bronchial edema at 3 mg/kg. Furthermore, BAY 61-3606 attenuated antigen-induced airway inflammation in rats. Based on these anti-inflammatory effects of BAY 61-3606 both in vitro and in vivo, it was demonstrated that Syk may play a very critical role in the pathogenesis of allergic reactions.

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

“…BAY61-3606 was selected over other Syk inhibitors because it has been shown previously to inhibit Syk activity in vivo in rodents (54,55). We observed that BAY61-3606 significantly reduces brain A␤ 38 , A␤ 40 , and A␤ 42 levels in Tg PS1/ APPsw mice (Fig.…”

Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection

“…Importantly, BAY 61-3606 is very selective for Syk at the concentrations used (68). We first assessed the effects of Syk inhibition on DENV-2 replication by measuring intracellular DENV E-protein expression in ADE-inoculated monocytes at 24 hpi (Fig.…”

Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases

“…R112 is another Syk inhibitor formulated for intranasal use [39] and has a rapid effect and quickly inhibits mast cell activation. Additional Syk inhibitors with less specificity include piceatannol and BAY 61-3606 [40,41]. …”

“…Alternatively, targeting the intracellular signaling cascade may represent an attractive approach. Appropriately, protein tyrosine kinases such as Syk, Lyn, and Btk have been directly implicated in IgE-dependent mast cell activation and have been suggested as targets for therapeutic intervention [39-41]. Syk represents the most attractive target because studies with mast cells derived from Syk-deficient indicated mice showed that Syk is important in the activation of mediators of degranulation, eicosanoid, and cytokine production [23,39].…”

“…But piceatannol did not inhibit exogenous arachidonic acid-induced release of peptidoleukotrienes from lung fragments. In an antigen-induced airway inflammation model in rodents, the Syk inhibitor BAY 61-3606 blocked both degranulation and lipid mediator and cytokine synthesis in mast cells and suppressed antigen-induced passive coetaneous reaction, bronchoconstriction, bronchial edema, and airway inflammation [41]. …”