A novel dual regulator of tumor necrosis factor-alpha and interleukin-10 protects mice from endotoxin-induced shock

A pyrimidylpiperazine derivative, N-[1-(4-([4-(pyrimidin-2-yl)piperazin-1-y l]methyl)phenyl)cyclopropyl]acetamide (Y-39041), is a dual cytokine regulat or of tumor necrosis factor(TNF)-alpha and interleukin-10 production. Lipop olysaccharide-induced TNF-alpha release in BALB/c mice was inhibited by the oral treatment with the compound at 10-100 mg/kg (about 80% suppression) w hile interleukin-10 release was augmented (about 10-fold increase at 30 mg/ kg). In addition, Y-39041 (30 mg/kg, p.o.) completely protected mice from l ipopolysaccharide-induced death by the treatment before and after Lipopolys accharide injection. The finding that Y-39041 suppresses TNF-alpha producti on and stimulates interleukin-10 production at the same time provides new i nsights for the treatment of septic shock, rheumatoid arthritis and Crohn's diseases. (C) 2000 Elsevier Science B.V. All rights reserved.