Design, Synthesis, and Biological Evaluation of the Novel Neutrophil Elastase Inhibitor CHF-6333 for the Inhaled Treatment of Bronchiectasis

The inhibitors of neutrophil elastase
(NE) have long
attracted
interest for the treatment of respiratory diseases. We report the
breakthrough of a new potent, selective NE inhibitor with a 24 h duration
of action: CHF-6333, is currently undergoing clinical studies for
the inhaled treatment of bronchiectasis (BE). The story of the discovery
project to identify novel small molecules that inhibit extracellular
elastase in the lung with prolonged activity is described. Medicinal
chemistry investigation, supported by docking studies, led to N-quaternary
compounds with an in vitro profile suitable for inhalatory
administration. Compound 15 emerged from in vivo pharmacokinetic and pharmacodynamic studies, also showing safety
and no off-target effects in vitro. Salt screening
of different counterions, in conjunction with in vivo local irritancy testing, aided in the selection of compound 15-xinafoate (CHF-6333). Efficacy in a lung injury model and
no findings in non-GLP toxicity studies promoted CHF-6333 as a clinical
candidate.