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YM-58483, a Selective CRAC Channel Inhibitor, Prevents Antigen-Induced Airway Eosinophilia and Late Phase Asthmatic Responses via Th2 Cytokine Inhibition in Animal Models

YM-58483, a Selective CRAC Channel Inhibitor, Prevents Antigen-Induced Airway Eosinophilia and Late Phase Asthmatic Responses via Th2 Cytokine Inhibition in Animal Models

Taiji Yoshino, Jun Ishikawa, Keiko Ohga, Tatsuaki Morokata, Ryuichi Takezawa, Hiroki Morio, Youhei Okada, Kazuo Honda, Toshimitsu Yamada

Eur J Pharmacol. 2007 Apr 10;560(2-3):225-33.

PMID: 17307161

Abstract:

T cells play a regulatory role in the pathogenesis of various immune and allergic diseases, including human asthma. Recently, it was reported that a pyrazole derivative, YM-58483 (BTP2), potently inhibits Ca(2+) release-activated Ca(2+) (CRAC) channels and interleukin (IL)-2 production in T cells. We investigated the effects of YM-58483 on T helper type 2 (Th2) cytokine production in vitro and antigen-induced airway asthmatic responses in vivo. YM-58483 inhibited IL-4 and IL-5 production in a conalbumine-stimulated murine Th2 T cell clone (D10.G4.1), and IL-5 production in phytohemagglutinin-stimulated human whole blood cells with IC(50) values comparable to those reported for its CRAC channel inhibition (around 100 nM). YM-58483 inhibited antigen-induced eosinophil infiltration into airways, and decreased IL-4 and cysteinyl-leukotrienes content in inflammatory airways induced in actively sensitized Brown Norway rats. Furthermore, orally administered YM-58483 prevented antigen-induced late phase asthmatic bronchoconstriction and eosinophil infiltration in actively sensitized guinea pigs. These data suggest that the inhibition of Ca(2+) influx through CRAC channel leads to the prevention of antigen-induced airway inflammation, probably via the inhibition of Th2 cytokine production and inflammatory mediators release. YM-58483 may therefore be useful for treating airway inflammation in bronchial asthma.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP223499307-B	YM-58483		223499-30-7	Price

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