title: Optimization of N-benzoylindazole derivatives as inhibitors of human neutrophil elastase.
abstract: Human neutrophil elastase (HNE) is an important therapeutic target for treatment of pulmonary diseases. Previously, we identified novel N-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 20f (IC50 ∼10 nM) and modifications at position 3 resulted the most potent compound in this series, the 3-CN derivative 5b (IC50 = 7 nM); both derivatives demonstrated good stability and specificity for HNE versus other serine proteases. Molecular docking of selected N-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.
authors.affiliation: NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.forename: Alessia
authors.initials: A
authors.lastname: Graziano
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.forename: Donatella
authors.initials: D
authors.lastname: Giomi
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Khlebnikov
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
mesh_terms: D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D001565:Benzoates; D007191:Indazoles; D019272:Leukocyte Elastase