Background:

IC50: 44 nM

Sivelestat (ONO-5046) is a neutrophil elastase inhibitor.

Human neutrophil elastase is a protease that hydrolyzes most connective tissue components, and it has been reported to participate in the tissue injury of rheumatoid arthritis, emphysema, adult respiratory distress syndrome as well as septic shock.

In vitro: Sivelestat was found to be able to competitively inhibit the human neutrophil elastase, and it could inhibit leukocyte elastase from rat, rabbit, mouse and hamster. Whereas, sivelestat even at 100 microM could not inhibit thrombin, plasmin, trypsin, pancreas kallikrein, plasma kallikrein, chymotrypsin and cathepsin G [1].

In vivo: In animal study, 50 or 100 mg/kg sivelestat were immediately administered by i.p. injection after the surgical procedure to male Sprague-Dawley rats with bacterial infection caused by cecal ligation and puncture. Results showed that in the untreated rats, the mean arterial pressure(MAP) and glomerular filtration rate(GFR) decreased, while serum blood urea nitrogen(BUN) and neutrophil gelatinase-associated lipocalin(NGAL) levels increased. Sivelestat was found to promot the survival of the rats with sepsis, restored the impairment of MAP and GFR, and inhibited the increased BUN and NGAL levels. In addition, sivelestat could suppress the CLP-induced macrophage infiltration in the rats [2].

Clinical trial: In Japan and the Republic of Korea, sivelestat has been approved for acute lung injury, such as acute respiratory distress syndrome in patients with systemic inflammatory response syndrome [3].

参考文献:
[1] Kawabata K,Suzuki M,Sugitani M,Imaki K,Toda M,Miyamoto T.  ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun.1991 Jun 14;177(2):814-20.
[2] Li G,Jia J,Ji K,Gong X,Wang R,Zhang X,Wang H,Zang B.  The neutrophil elastase inhibitor, sivelestat, attenuates sepsis-related kidney injury in rats. Int J Mol Med.2016 Sep;38(3):767-75.
[3] Aikawa N,Kawasaki Y.  Clinical utility of the neutrophil elastase inhibitor sivelestat for the treatment of acute respiratory distress syndrome. Ther Clin Risk Manag.2014 Aug 5;10:621-9.