Selection of Novel Analogs of Thalidomide with Enhanced Tumor Necrosis Factor α Inhibitory Activity

Tumor necrosis factor α (TNFα) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (α-n–phthalimidoglutarimide) was shown to partially inhibit monocyte TNFα production (by 50–70%) both in vivo and in vitro. More efficient inhibition of TNFα may, however, be necessary to rescue the host from more acute and extensive toxicities of TNFα-mediated inflammation. Three structural analogues of thalidomide were selected for study based on increased activity against TNFα production. The parent drug and the analogs were tested in vitro in human peripheral blood mononuclear cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot hybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality. The new compounds (two esters and one amide) showed increased inhibition of TNFα production by LPS-stimulated human monocytes, relative to the parent drug thalidomide. The analogs and the parent drug enhanced the production of interleukin 10 (IL-10), but had little effect on IL-6 and IL-1β protein and mRNA production. When tested in vivo, the amide analog protected 80% of LPS-treated mice against death from endotoxin induced shock. Analogs of thalidomide designed to better inhibit TNFα production in vitro have correspondingly greater efficacy in vivo. These finding may have therapeutic implication for the treatment of human diseases characterized by acute and extensive TNFα production such as tuberculous meningitis or toxic shock.