Lipopolysaccharide (LPS) is critically involved in the inflammatory responses via generation of several pro-inflammatory cytokines. Since tumor necrosis factor-alpha (TNF-alpha) is one of the major pro-inflammatory cytokines which is induced by LPS treatment, the development of molecules capable of modulating LPS-induced TNF-alpha production is an issue of concern. We identified a novel synthetic compound that inhibits LPS-induced TNF-alpha production in human peripheral blood mononuclear cells (PBMCs). The active compound SM-7409 inhibited LPS-induced TNF-alpha production in a concentration-dependent manner, showing maximal activity at 5 mu M. SM-7409 inhibited LPS-induced TNF-alpha mRNA transcript accumulation and protein expression. We also found that SM-7409 strongly inhibits LPS-induced extracellular signal-regulated protein kinase activity in PBMCs. Moreover, we found that SM-7409 strongly inhibits the LPS-induced other pro-inflammatory cytokines, such as interleukin (IL)-1 beta and IL-8 in PBMCs. SM-7409 also dramatically inhibits the LPS-induced TNF-alpha production in neutrophils. Taken together, our results demonstrate that SM-7409 is a synthetic compound that inhibits LPS-induced TNF-alpha production, and thus SM-7409 should be useful for the development of chemotherapies targeting LPS-mediated inflammatory responses. (c) 2006 Elsevier Inc. All rights reserved.