SELECTION OF NOVEL ANALOGS OF THALIDOMIDE WITH ENHANCED TUMOR-NECROSIS-FACTOR-ALPHA INHIBITORY ACTIVITY

Background: Tumor necrosis factor or (TNF alpha) is thought to mediate both protective and detrimental manifestations of the inflammatory re sponse. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was sho wn to partially inhibit monocyte TNF alpha production (by 50-70%) both in vivo and in vitro. More efficient inhibition of TNF alpha may, how ever, be necessary to rescue the host from more acute and extensive to xicities of TNF alpha-mediated inflammation. Materials and Methods: Th ree structural analogues of thalidomide were selected for study based on increased activity against TNF alpha production. The parent drug an d the analogs were tested in vitro in human peripheral blood mononucle ar cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot h ybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality. Results: The new comp ounds (two esters and one amide) showed increased inhibition of TNF al pha production by LPS-stimulated human monocytes, relative to the pare nt drug thalidomide. The analogs and the parent drug enhanced the prod uction of interleukin 10 (IL-10), but had little effect on IL-6 and IL -1 beta protein and mRNA production. When tested in vivo, the amide an alog protected 80% of LPS-treated mice against death from endotoxin in duced shock. Conclusions: Analogs of thalidomide designed to better in hibit TNF alpha production in vitro have correspondingly greater effic acy in vivo. These finding may have therapeutic implication for the tr eatment of human diseases characterized by acute and extensive TNF alp ha production such as tuberculous meningitis or toxic shock.