title: 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.
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 (100mg/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.
authors.affiliation: Pharmacology Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. keiko.ohga@jp.astellas.com
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohga
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Takezawa
authors.forename: Taiji
authors.initials: T
authors.lastname: Yoshino
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Yamada
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Jun
authors.initials: J
authors.lastname: Ishikawa
mesh_terms: D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000517:prevention & control; D016084:Bronchoconstriction / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004140:Dinitrophenols / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000096:biosynthesis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D010047:Ovalbumin / Q000276:immunology; D010835:Phytohemagglutinins / Q000276:immunology; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D012710:Serum Albumin, Bovine / Q000276:immunology; D013830:Thiadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology
chemical_list: C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D000893:Anti-Inflammatory Agents; D002121:Calcium Channel Blockers; D004140:Dinitrophenols; D015289:Leukotrienes; D010835:Phytohemagglutinins; D013830:Thiadiazoles; C034638:dinitrophenyl-bovine serum albumin; C028784:phytohemagglutinin-P; D012710:Serum Albumin, Bovine; D010047:Ovalbumin; D011239:Prednisolone; D002118:Calcium