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 (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.

• Authors: Noriyuki Yamamoto, Keisuke Takeshita, Michitaka Shichijo, Toshio Kokubo, Masako Sato, Kosuke Nakashima, Mina Ishimori, Hiroichi Nagai, Ying-Fu Li, Takeshi Yura, Kevin B Bacon
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 306 Issue 3 Pg. 1174-81 (Sep 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12766258 (Publication Type: Journal Article)

Chemical References

• 2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
• Enzyme Inhibitors
• Pyrimidines
• Niacinamide
• Protein-Tyrosine Kinases

Topics

• Administration, Oral
• Animals
• Bronchoconstriction (drug effects)
• Edema (chemically induced, prevention & control)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Humans
• In Vitro Techniques
• Inflammation (chemically induced, prevention & control)
• Mast Cells (drug effects, physiology)
• Mice
• Mice, Transgenic
• Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (pharmacology, therapeutic use)
• Rats
• Spleen (enzymology)