Syk inhibitors as treatment for allergic rhinitis

被引:59
作者
Masuda, Esteban S. [1 ]
Schmitz, Jochen [1 ]
机构
[1] Rigel Inc, San Francisco, CA 94080 USA
关键词
Allergic rhinitis; Syk; Kinase inhibitor; Mast cells; IgE receptor;
D O I
10.1016/j.pupt.2007.06.002
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 immunoglubulin 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 RI 12, 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 or acute allergic rhinitis symptoms with rapid onset of action. These results demonstrate the clinical significance of inhibiting Syk in allergic upper airway disorders. (C) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码:461 / 467
页数:7
相关论文
共 54 条
[1]   Corticosteroids: The drugs to beat [J].
Barnes, PJ .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2006, 533 (1-3) :2-14
[2]   Novel signal transduction modulators for the treatment of airway diseases [J].
Barnes, PJ .
PHARMACOLOGY & THERAPEUTICS, 2006, 109 (1-2) :238-245
[3]   NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway [J].
Billadeau, DD ;
Upshaw, JL ;
Schoon, RA ;
Dick, CJ ;
Leibson, PJ .
NATURE IMMUNOLOGY, 2003, 4 (06) :557-564
[4]   Targeting kinases in asthma [J].
Blease, K .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2005, 14 (10) :1213-1220
[5]   Remission of allergic rhinitis: An 8-year observational study [J].
Bodtger, U ;
Linneberg, A .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2004, 114 (06) :1384-1388
[6]  
Bousquet J, 2004, ALLERGY, V59, P373
[7]   RETRACTED: The IL-15Rα chain signals through association with Syk in human B cells (Retracted article. See vol. 186, pg. 2681, 2011) [J].
Bulanova, E ;
Budagian, V ;
Pohl, T ;
Krause, H ;
Dürkop, H ;
Paus, R ;
Bulfone-Paus, S .
JOURNAL OF IMMUNOLOGY, 2001, 167 (11) :6292-6302
[8]   A novel spleen tyrosine kinase inhibitor blocks c-jun N-terminal kinase-mediated gene expression in synoviocytes [J].
Cha, HS ;
Boyle, DL ;
Inoue, T ;
Schoot, R ;
Tak, PP ;
Pine, P ;
Firestein, GS .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 317 (02) :571-578
[9]   Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis [J].
Chervinsky, P ;
Casale, T ;
Townley, R ;
Tripathy, I ;
Hedgecock, S ;
Fowler-Taylor, A ;
Shen, H ;
Fox, H .
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY, 2003, 91 (02) :160-167
[10]  
CHURCH MK, 2003, MIDDLETONS ALLERGY P, V1, P189