A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice

Journal of Pharmacological Sciences

Hyuk Soon Kim¹  Jun Ho Lee¹  Wahn Soo Choi¹  Bo Kyung Kim¹  Hye-Jin Park²  Kyu Yang Yi³  A-Ram Kim¹  Jie Wan Kim¹  Do Kyun Kim¹  Dong Ki Park² 

[1] Institutes of Functional Genomics and College of Medicine, Konkuk University, Korea;Department of Bioscience and Biotechnology, Konkuk University, Korea;Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Korea

关键词: 3-butyl-1-chloro-8-(2-methoxycarbonyl)phenyl-5H-imidazo[1;    5-b]isoquinolin-10-one (U63A05);    mast cell;    IgE;    type I hypersensitive response;    syk;   

DOI  :  10.1254/jphs.10300FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(32)Cited-By(4)Mast cells play a pivotal role in IgE-mediated allergic responses. Development of specific inhibitors against FcεRI-associated proximal signaling molecules in mast cells may represent a promising therapeutic strategy for allergic diseases. We examined whether a novel synthetic compound, 3-butyl-1-chloro-8-(2-methoxycarbonyl)phenyl-5H-imidazo[1,5-b]isoquinolin-10-one (U63A05), could suppress antigen-stimulated degranulation and cytokine secretion in mast cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. U63A05 reversibly and dose-dependently inhibited degranulation of rat basophilic leukemia (RBL)-2H3 mast cells and bone marrow–derived mast cells (BMMCs) stimulated by antigen (IC50 values for RBL-2H3 and BMMCs were 4.1 and 4.8 μM, respectively). The secretion of inflammatory cytokines was also suppressed in antigen-stimulated mast cells. However, degranulation by thapsigargin, a typical calcium inducer, was not inhibited by U63A05. U63A05 exerts its inhibitory effect, to the same extent as in degranulation, on the activating phosphorylation of Syk and downstream signaling molecules, including LAT and SLP-76. Further downstream, the activating phosphorylations of Akt, Erk1/2, p38, and JNK were also inhibited. Finally, antigen-stimulated PCA was dose-dependently suppressed in mice (ED50, 26.3 mg/kg). Taken together, the results suggest that U63A05 suppresses the activation of mast cells and the mast cell–mediated allergic response through the inhibition of Syk activation in mast cells.

【 授权许可】

Unknown