title: LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model.
abstract: As part of a program researching the synthesis and immunopharmacological evaluation of novel synthetic compounds, we have described the immune modulatory profile of the new achiral thalidomide analogue LASSBio-468 in the present work. This compound was planned as an N-substituted phthalimide derivate, structurally designed as a hybrid of thalidomide and aryl sulfonamides, which were previously described as tumor necrosis factor-alpha (TNF-alpha) and PDE4 inhibitors. LASSBio-468 was recently demonstrated to inhibit the TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Here, we investigated whether this compound would affect chronic inflammation processes associated with the production of this pro-inflammatory cytokine. Treatment with LASSBio-468 before a lethal dose injection of LPS in animals greatly inhibited endotoxic shock. This effect seems to be mediated by a specific down regulation of TNF-alpha and nitric oxide production, regulated mainly at the RNA level. In another model, histopathological analysis indicated that this compound also inhibited adjuvant-induced arthritis in rats. Taken together, our data demonstrated a potent anti-inflammatory effect of LASSBio-468, suggesting its use as a potential drug against chronic inflammatory diseases.
authors.affiliation: LASSBio-Laboratório de Avaliação e Síntese de Substâncias Bioativas, Departamento de Fármacos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, CP 68.006, ZIP 21944-910, Rio de Janeiro, R.J., Brazil.
authors.forename: Magna S
authors.initials: MS
authors.lastname: Alexandre-Moreira
authors.forename: Christina M
authors.initials: CM
authors.lastname: Takiya
authors.forename: Luciana B
authors.initials: LB
authors.lastname: de Arruda
authors.forename: Bernardo
authors.initials: B
authors.lastname: Pascarelli
authors.forename: Raquel N
authors.initials: RN
authors.lastname: Gomes
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro Faria Neto
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Lima
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000097:blood* / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000188:drug therapy*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020293:Vasculitis, Central Nervous System / Q000188:drug therapy / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D007211:Indoles; D054833:Isoindoles; C503834:LASSBio-468; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013792:Thalidomide; D010431:Pentoxifylline