Optimization
of <i>N</i>‑Benzoylindazole
Derivatives as Inhibitors of Human Neutrophil Elastase
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Abstract
Human
neutrophil elastase (HNE) is an important therapeutic target
for treatment of pulmonary diseases. Previously, we identified novel <i>N</i>-benzoylindazole derivatives as potent, competitive, and
pseudoirreversible HNE inhibitors. Here, we report further development
of these inhibitors with improved potency, protease selectivity, and
stability compared to our previous leads. Introduction of a variety
of substituents at position 5 of the indazole resulted in the potent
inhibitor <b>20f</b> (IC<sub>50</sub> ∼10 nM) and modifications
at position 3 resulted the most potent compound in this series, the
3-CN derivative <b>5b</b> (IC<sub>50</sub> = 7 nM); both derivatives
demonstrated good stability and specificity for HNE versus other serine
proteases. Molecular docking of selected <i>N</i>-benzoylindazoles
into the HNE binding domain suggested that inhibitory activity depended
on geometry of the ligand–enzyme complexes. Indeed, the ability
of a ligand to form a Michaelis complex and favorable conditions for
proton transfer between Hys57, Asp102, and Ser195 both affected activity