N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride inhibits LPS-induced TNF-alpha production and improves survival in endotoxemic mice

N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride, was examin ed for its effect on TNF-alpha production by human myeloid THP-1 cells stim ulated with lipopolysaccharide (EPS). N2733 inhibited LPS-induced release o f TNF-alpha from THP-1 cells with an IC50 of 11 mu M. N2733 did not affect the cell viability at the concentration of 50 mu M or 100 mu M. This indica tes that N2733 is a potent inhibitor for TNF-alpha production without sever e cytotoxicity. N2733 was also studied in two murine endotoxin shock models induced with LPS. One model was DBA/2 mice injected with LPS (5.6 mg/kg, i .v.), which increased the serum level of TNF-alpha within 1 hr. Treatment o f these mice with N2733 (100 mg/kg x 2, i.p.) decreased the serum level of TNF-alpha significantly. Another model was DBA/2 mice induced with LPS (30 mg/kg, i.v.), which reduced the survival rate to 30% during 7 days. Adminis trations of 30 mg/kg and 100 mg/kg N2733 (i.v.) restored the survival rates to 60% and 90% respectively. Our data demonstrate that N2733 inhibits LPS- induced TNF-alpha production, and this response is associated with an impro vement in the survival rate of endotoxemic mice.