Sivelestat (ONO5046) is a potent and selective inhibitor of neutrophil elastase with IC50 of 44 nM.

Neutrophil elastase:44 nM.

Sivelestat suppresses iNOS gene expression in proinflammatory cytokine-stimulated hepatocytes. Sivelestat reduces the levels of inflammatory mediators by inhibiting NF-kB. It suppresses the growth of gastric cancer cells by inhibiting the release of TGF-α stimulated by NE.

Administration of sivelestat attenuates pulmonary fibrosis after acute lung injury in mice. Sivelestat could attenuate sepsis-related kidney injury in rats. It blocks GAPDH/Siah1 which is a novel signaling pathway during the progression of spinal cord injury.

TMK-1 Gastric carcinoma cells are seeded into 96-well culture plates (5 ×103 cells/well) in RPMI containing 7% FBS, 2.0 mM L-glutamine, and 1% nonessential amino acids. Following 24-h incubation in RPMI-1640 medium with 5% FBS, the cells are incubated for 24, 48 or 72 h at 37°C in a humidified atmosphere of 5% CO2 with varied concentrations (0.1–1.0 μg/mL) of NE, or with varied concentrations (0.1–1000 μg/mL) of sivelestat or with concentrations (10 and 100 ng/mL) of anti-TGF-α antibody in the presence of 1 μg/mL NE. After incubation, 10 μL of MTT solution (5 mg/mL) is added to each well and the plates are then incubated for 3 h at 37°C. The growth medium is then replaced with 150 μL of dimethyl sulfoxide (Wako) per well and the absorbance at 540 nm is measured.

Animal Models: Male Sprague-Dawley rats. Formulation: Saline. Dosages: 50 or 100 mg/kg. Administration: i.p.