Syk inhibitors as treatment for allergic rhinitis.
Allergic rhinitis is characterized by a hypersensitive immune response in the upper airways to seasonal or perennial allergens leading to episodes of sneezing, itching, runny nose and nasal congestion. These symptoms are mainly the manifestations of a large number of mediators released by mast cells and basophils localized in the nasal mucosa, following their activation via allergen-specific immunoglobulin E (IgE) receptors. Current medications antagonize the action of distinct mediators such as histamine and leukotrienes for symptom relief, or block the production of pro-inflammatory cytokines to suppress allergic inflammation. Notably, rather than neutralizing individual mediators, Syk kinase inhibitors can block the allergen-induced release of all mast cell mediators and the production of most eicosanoids and cytokines. Thus, Syk kinase represents an attractive therapeutic target for acute and chronic allergic inflammation. Syk kinase inhibitors are now entering clinical trials. Using cell-based structure-activity relationships with primary human mast cells, a series of 2,4-diaminopyrimidine Syk kinase inhibitors was developed. One of these compounds, referred to as R112, exhibited suitable characteristics for intranasal delivery and was tested for safety and efficacy in allergic rhinitis patients. In a park environment, R112 showed remarkable amelioration of acute allergic rhinitis symptoms with rapid onset of action. These results demonstrate the clinical significance of inhibiting Syk in allergic upper airway disorders.
Masuda
Esteban S
ES
Rigel Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. emasuda@rigel.com <emasuda@rigel.com>
Schmitz
Jochen
J
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007073:Immunoglobulin E / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D017455:Receptors, IgE / Q000187:drug effects / Q000502:physiology; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase
D018926:Anti-Allergic Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017455:Receptors, IgE; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase