TY - JOUR T1 - AZD9668: pharmacological characterisation of a novel oral inhibitor of neutrophil elastase JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.182139 SP - jpet.111.182139 AU - Tim Stevens AU - Kjell Ekholm AU - Mia Granse AU - Maria Lindahl AU - Viktoria Kozma AU - Christina Jungar AU - Tomas Ottosson AU - Hanna Falk-Hakansson AU - Andrew Churg AU - Joanne L Wright AU - Harbans Lal AU - Annika Sanfridson Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/08/05/jpet.111.182139.abstract N2 - AZD9668 is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction and lung tissue damage. In vitro and in vivo experiments were evaluated the binding kinetics, potency and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good cross-over potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung haemorrhage, and an increase in matrix protein degradation products in broncho-alveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1β. Finally, AZD9668 prevented airspace enlargement and small airway wall remodelling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases. ER -