The suppressive effects of YM-58483/BTP-2, a store-operated Ca2+ entry blocker, on inflammatory mediator release in vitro and airway responses in vivo

• Published in: Pulmonary pharmacology & therapeutics 2008-01, Vol.21 (2), p.360-369
• Main Authors: Ohga, Keiko, Takezawa, Ryuichi, Yoshino, Taiji, Yamada, Toshimitsu, Shimizu, Yasuaki, Ishikawa, Jun
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Anilides - therapeutic use; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Blood Cells - drug effects; Blood Cells - metabolism; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - prevention & control; Bronchoconstriction - drug effects; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; Cell Line; Dinitrophenols - immunology; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Release - drug effects; Humans; In Vitro Techniques; Leukotrienes - biosynthesis; Male; Medical Education; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - immunology; Muscle, Smooth - physiopathology; Ovalbumin - immunology; Phytohemagglutinins - immunology; Prednisolone - pharmacology; Prednisolone - therapeutic use; Pulmonary/Respiratory; Rats; Serum Albumin, Bovine - immunology; Thiadiazoles - pharmacology; Thiadiazoles - therapeutic use; Trachea - drug effects; Trachea - immunology; Trachea - physiopathology
• ISSN: 1094-5539
• DOI: 10.1016/j.pupt.2007.09.003

Abstract YM-58483/BTP-2, 4-methyl-4′-[3,5- bis (trifluoromethyl)-1H-pyrazol-1- yl ]-1,2,3-thiadiazole-5-carboxanilide, blocks the store-operated Ca2+ entry (SOCE) that mediates the activation of non-excitable cells. This study investigated the pharmacological profile and therapeutic potential of YM-58483 as anti-asthma drug. YM-58483 inhibited DNP antigen-induced histamine release from and leukotrienes (LTs) production in IgE-primed RBL-2H3 cells, a rat basophilic leukemia cell line, with IC50 values of 460 and 310 nM, respectively. Prednisolone did not inhibit either of these responses. YM-58483 also inhibited phytohemagglutinin-P (PHA)-stimulated IL-5 and IL-13 production in human peripheral blood cells with IC50 values of 125 and 148 nM, respectively, which is approximately 5 times less potent than prednisolone. YM-58483 (30 mg/kg, p.o.) significantly suppressed ovalbumin (OVA)-induced bronchoconstriction in OVA-sensitized guinea pigs, whereas prednisolone did not. YM-58483 (3–30 mg/kg, p.o.) and prednisolone (100 mg/kg, p.o.) both significantly and completely suppressed airway hyperresponsiveness (AHR) caused by OVA exposure. Since YM-58483 inhibits two major characteristic symptoms of bronchial asthma, namely bronchoconstriction and AHR via the suppression of inflammatory mediator and cytokine production, SOCE inhibition is a potential approach for treatment.