LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model

Int Immunopharmacol. 2005 Mar;5(3):485-94. doi: 10.1016/j.intimp.2004.10.017.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / pathology
  • Gene Expression / drug effects
  • Indoles / pharmacology*
  • Isoindoles
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation / drug effects
  • Macrophages, Peritoneal / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Nitric Oxide / blood*
  • Nitric Oxide / metabolism
  • Pentoxifylline / pharmacology
  • Rats
  • Rats, Wistar
  • Shock, Septic / drug therapy*
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vasculitis, Central Nervous System / drug therapy
  • Vasculitis, Central Nervous System / pathology

Substances

  • Anti-Inflammatory Agents
  • Indoles
  • Isoindoles
  • LASSBio-468
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Thalidomide
  • Pentoxifylline