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.
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.
Yamamoto
Noriyuki
N
Research Center Kyoto, Bayer Yakuhin, Ltd, Japan. noriyuki.yamamoto.ny@bayer.co.jp
Takeshita
Keisuke
K
Shichijo
Michitaka
M
Kokubo
Toshio
T
Sato
Masako
M
Nakashima
Kosuke
K
Ishimori
Mina
M
Nagai
Hiroichi
H
Li
Ying-Fu
YF
Yura
Takeshi
T
Bacon
Kevin B
KB
D000284:Administration, Oral; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013154:Spleen / Q000201:enzymology
C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D009536:Niacinamide; D011505:Protein-Tyrosine Kinases