PT  - JOURNAL ARTICLE
AU  - Noriyuki Yamamoto
AU  - Keisuke Takeshita
AU  - Michitaka Shichijo
AU  - Toshio Kokubo
AU  - Masako Sato
AU  - Kosuke Nakashima
AU  - Mina Ishimori
AU  - Hiroichi Nagai
AU  - Ying-Fu Li
AU  - Takeshi Yura
AU  - Kevin B. Bacon
TI  - The Orally Available Spleen Tyrosine Kinase Inhibitor
 2-[7-(3,4-Dimethoxyphenyl)-imidazo[1,2-<em>c</em>]pyrimidin-5-ylamino]nicotinamide
 Dihydrochloride (BAY 61-3606) Blocks Antigen-Induced Airway Inflammation in
 Rodents
AID  - 10.1124/jpet.103.052316
DP  - 2003 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1174--1181
VI  - 306
IP  - 3
4099  - http://jpet.aspetjournals.org/content/306/3/1174.short
4100  - http://jpet.aspetjournals.org/content/306/3/1174.full
SO  - J Pharmacol Exp Ther2003 Sep 01; 306
AB  - 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 (Ki = 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. The American Society for Pharmacology and Experimental Therapeutics