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.
Footnotes
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N.Y. and K.T. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.052316.
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ABBREVIATIONS: Syk, spleen tyrosine kinase; FcϵRI, high affinity type-I receptor for IgE; FcγR, receptors for Fc portion of IgG; FcR, receptors for Fc portion of immunoglobulins; BAL, bronchoalveolar lavage; OVA, ovalbumin; BAY 61-3606, 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-nicotinamide dihydrochloride; LT, leukotriene; GM-CSF, granulocyte-macrophage colony-stimulating factor; ELISA, enzyme-linked immunosorbent assay; PGD2, prostaglandin D2; IL, interleukin; DNP, dinitrophenol; DNP-BSA, dinitrophenol-bovine serum albumin; His, histidine6; PIPES, piperazine-N,N′-bis(2-ethanesulfonic acid); BSA, bovine serum albumin; HCMC, human cultured mast cell; PCA, passive cutaneous anaphylaxis; DSCG, disodium cromoglycate; BCR, B cell receptor complex.
- Received April 1, 2003.
- Accepted May 20, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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