Pharmacological characterization of CHI25243, a novel potent inhaled inhibitor of neutrophil elastase

Neutrophil elastase (NE) is a key proteolytic enzyme implicated in the pathogenesis of chronic inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD), bronchiectasis and cystic fibrosis (CF). Here we studied the pharmacological profile of CHI25243, a novel NE inhibitor designed for inhaled treatment of NE-driven lung diseases. In in vitro assays, CHI25243 shows a high potency in inhibiting human NE (IC₅₀=0.2nM), conserved across species (rat, IC₅₀=4.1nM; dog, IC₅₀=7.9nM), with more than 100-fold selectivity against other proteases. The in vivo effects of CHI25243 were studied in two rat models: human NE-induced lung injury and LPS-fMLP induced NE release. When administered intratracheally (i.t.), CHI25243 prevents human NE-induced lung haemorrhage with an ED₅₀ of 74µg/kg, while in the LPS-fMLP model it shows a potent, dose-dependent and long-lasting (up to 24h) inhibition of elastase activity (with 30µg/kg being the minimum dose providing 24h efficacy). In addition, CHI25243 shows efficacy in relevant disease models. Specifically, it significantly reduces lung neutrophil recruitment induced by 4-day cigarette smoke exposure in mice with a minimum effective dose (MED) of 100µg/kg. CHI25243administered i.t. to P. aeruginosa lung infected rats for 7 days, significantly reduces both lung tissue infection and inflammation with a MED of 100 µg/kg. Our data support the development of CHI25243, a novel potent and selective inhaled NE inhibitor, which is capable of inhibiting both pulmonary inflammation and infection in various preclinical animal models, thus suggesting the potential for the treatment of chronic inflammatory lung diseases.