title: A pyrazole derivative, YM-58483, potently inhibits store-operated sustained Ca2+ influx and IL-2 production in T lymphocytes.
abstract: In nonexcitable cells, Ca(2+) entry is mediated predominantly through the store depletion-dependent Ca(2+) channels called store-operated Ca(2+) (SOC) or Ca(2+) release-activated Ca(2+) channels. YM-58483, a pyrazole derivative, inhibited an anti-CD3 mAb-induced sustained Ca(2+) influx in acute T cell leukemia, Jurkat cells. But it did not affect an anti-CD3 mAb-induced transient intracellular Ca(2+) increase in Ca(2+)-free medium, nor anti-CD3 mAb-induced phosphorylation of phospholipase Cgamma1. It was suggested that YM-58483 inhibited Ca(2+) influx through SOC channels without affecting the TCR signal transduction cascade. Furthermore, YM-58483 inhibited thapsigargin-induced sustained Ca(2+) influx with an IC(50) value of 100 nM without affecting membrane potential. YM-58483 inhibited by 30-fold the Ca(2+) influx through SOC channels compared with voltage-operated Ca(2+) channels, while econazole inhibited both SOC channels and voltage-operated Ca(2+) channels with an equivalent range of IC(50) values. YM-58483 potently inhibited IL-2 production and NF-AT-driven promoter activity, but not AP-1-driven promoter activity in Jurkat cells. Moreover, this compound inhibited delayed-type hypersensitivity in mice with an ED(50) of 1.1 mg/kg. Therefore, we concluded that YM-58483 was a novel store-operated Ca(2+) entry blocker and a potent immunomodulator, and could be useful for the treatment of autoimmune diseases and chronic inflammation. Furthermore, YM-58483 would be a candidate for the study of capacitative Ca(2+) entry mechanisms through SOC/CRAC channels and for identification of putative Ca(2+) channel genes.
authors.affiliation: Inflammation Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan. ishikaj@yamanouchi.co.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Ishikawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohga
authors.forename: Taiji
authors.initials: T
authors.lastname: Yoshino
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Takezawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kubota
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Yamada
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D007424:Intracellular Fluid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000276:immunology; D019169:Jurkat Cells; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D051379:Mice; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D016716:PC12 Cells; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology; D010853:Picryl Chloride / Q000008:administration & dosage; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010835:Phytohemagglutinins; D011720:Pyrazoles; D013830:Thiadiazoles; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014443:Tyrosine; D019284:Thapsigargin; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium; D010853:Picryl Chloride