title: Toll-like receptor 4 signal transduction inhibitor, M62812, suppresses endothelial cell and leukocyte activation and prevents lethal septic shock in mice.
abstract: Sepsis occurs when microbes activate toll-like receptors (TLRs) stimulating widespread inflammation and activating coagulation cascades. TLR4 signal transduction has been recognized as a key pathway for lipopolysaccharide (LPS)-induced activation of various cells and an attractive target for treatment of sepsis. We found a new benzisothiazole derivative, M62812 that inhibits TLR4 signal transduction. This compound suppressed LPS-induced upregulation of inflammatory cytokines, adhesion molecules and procoagulant activity in human vascular endothelial cells and peripheral mononuclear cells. The half maximal inhibitory concentrations in these assays ranged from 1 to 3 microg/ml. Single intravenous administration of M62812 (10-20 mg/kg) protected mice from lethality and reduced inflammatory and coagulatory parameters in a murine d-galactosamine-sensitized endotoxin shock model. M62812 (20 mg/kg) also prevented mice from lethality in a murine cecal ligation and puncture model. These results suggest that inhibition of TLR4 signal transduction can suppress coagulation as well as inflammation during sepsis and may be clinically beneficial in sepsis treatment.
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., LTD., Shizuoka 412-8524, Japan. mnakamur@mochida.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Sato
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Satoh
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kato
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosaka
authors.forename: Shoji
authors.initials: S
authors.lastname: Furusako
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004731:Endotoxins; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D014471:Umbilical Veins; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D004731:Endotoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C525083:M62812; D013844:Thiazoles; D051197:Toll-Like Receptor 4