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INFLAMMATION AND IMMUNOPHARMACOLOGY

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

Research Center Kyoto, Bayer Yakuhin, Ltd., Kyoto, Japan (N.Y., K.T., M.S., T.K., M.S., K.N., M.I., Y.-F.L., T.Y., K.B.B.); and Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan (H.N.)

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 = 7.5 nM) and selective inhibitor of Syk kinase. BAY 61-3606 inhibited not only degranulation (IC₅₀ 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 (IC₅₀ = 10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC₅₀ = 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.

Address correspondence to: Dr. Noriyuki Yamamoto, Research Center Kyoto, Bayer Yakuhin, Ltd., 6-5-1-3, Kunimidai, Kizu-cho, Soraku-gun, Kyoto 619-0216 Japan. E-mail: noriyuki.yamamoto.ny{at}bayer.co.jp

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