1. LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model.
- Author
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Alexandre-Moreira MS, Takiya CM, de Arruda LB, Pascarelli B, Gomes RN, Castro Faria Neto HC, Lima LM, and Barreiro EJ
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Arthritis, Experimental genetics, Arthritis, Experimental pathology, Gene Expression drug effects, Isoindoles, Lipopolysaccharides pharmacology, Lymphocyte Activation drug effects, Macrophages, Peritoneal drug effects, Male, Mice, Mice, Inbred BALB C, Nitric Oxide metabolism, Pentoxifylline pharmacology, Rats, Rats, Wistar, Thalidomide pharmacology, Tumor Necrosis Factor-alpha genetics, Vasculitis, Central Nervous System drug therapy, Vasculitis, Central Nervous System pathology, Arthritis, Experimental drug therapy, Indoles pharmacology, Nitric Oxide blood, Shock, Septic drug therapy, Thalidomide analogs & derivatives, Tumor Necrosis Factor-alpha metabolism
- 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.
- Published
- 2005
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