Neutrophil elastase inhibitors: recent advances in the development of mechanism-based and nonelectrophilic inhibitors.

Due to its implication in pathologies of prevalent diseases such as chronic obstructive pulmonary disease, fibrosis, bronchiectasis and ARDS, the serine protease, human neutrophil elastase, has been in focus for drug-development efforts over the last two decades. In recent years, continued efforts to identify and optimize novel mechanism-based inhibitors have led to a number of new inhibitors being reported. These compounds show promising potency and selectivity profiles, although their use is still limited by their inherent stability. Recently, two novel classes of potent and selective, synthetic, nonelectrophilic human neutrophil elastase inhibitors that display improved stability and overall drug-like properties have been reported. The most advanced compound from these classes, AZD9668, has been reported to show significant effects on relevant biomarkers in bronchiectasis and cystic fibrosis patient populations.