Freselestat quarterhydrate (ONO-6818 quarterhydrate) is a potent and orally active neutrophil elastase inhibitor with a Ki of 12.2 nM. Freselestat quarterhydrate is >100-fold less-active against other proteases such as trypsin, protein-ase 3, pancreatic elastase, plasmin, thrombin, collagenase, cathepsin G, and murine macrophage elastase. Freselestat quarterhydrate has a potent anti-inflammatory activity[1][2][3][4].
Simulated extracorporeal circulation is established by recirculating fresh heparinized (3.75 U/mL) human blood for 120 minutes in a membrane oxygenator and a roller pump with and without 1.0 μM of Freselestat (ONO-6818). Neutrophil elastase levels are significantly lower in the Freselestat group. Freselestat significantly reduces interleukin 8 and C5b-9 production. Freselestat does not modulate changes of CD11b and L-selectin during recirculation[3].
Freselestat (ONO-6818; 10-100 mg/kg; oral administration; daily; for 8 weeks) treatment attenuates dose-dependently HNE-induced increases in lung myeloperoxidase activity, hemoglobin, and neutrophil count in bronchoalveolar lavage fluid. ONO-6818 inhibits acute lung injury induced by HNE by minimizing lung hemorrhage and accumulation of neutrophils in the lung[1]. Animal Model: Male Wistar rats (228 g) induced by human neutrophil elastase (HNE)[1]
[1]. Am J Respir Crit Care Med. 2002 Aug 15;166(4):496-500. [2]. K Ohmoto, et al. Design and synthesis of new orally active inhibitors of human neutrophil elastase. Bioorg Med Chem. 2001 May;9(5):1307-23. [3]. Yasushi Hirota, et al. Effects of the neutrophil elastase inhibitor (ONO-6818) on acetic acid induced colitis in Syrian hamsters. J Vet Med Sci. 2004 Oct;66(10):1223-8. [4]. Yukihiro Yoshimura, et al. ONO-6818, a novel, potent neutrophil elastase inhibitor, reduces inflammatory mediators during simulated extracorporeal circulation. Ann Thorac Surg. 2003 Oct;76(4):1234-9.