Optimization of N-Benzoylindazole Derivatives as Inhibitors of Human Neutrophil Elastase

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• 作者：Letizia Crocetti ; Igor A. Schepetkin ; Agostino Cilibrizzi ; Alessia Graziano ; Claudia Vergelli ; Donatella Giomi ; Andrei I. Khlebnikov ; Mark T. Quinn ; Maria Paola Giovannoni
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 8, 2013
• 年：2013
• 卷：56
• 期：15
• 页码：6259-6272
• 全文大小：542K
• 年卷期：v.56,no.15(August 8, 2013)
• ISSN：1520-4804

文摘

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鈥揺nzyme 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.