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.
| Original language | English |
|---|---|
| Pages (from-to) | 6259-6272 |
| Number of pages | 14 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 56 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 8 Aug 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Optimization of N-benzoylindazole derivatives as inhibitors of human neutrophil elastase. / Crocetti, Letizia; Schepetkin, Igor A.; Cilibrizzi, Agostino; Graziano, Alessia; Vergelli, Claudia; Giomi, Donatella; Khlebnikov, Andrey Ivanovich; Quinn, Mark T.; Giovannoni, Maria Paola.
In: Journal of Medicinal Chemistry, Vol. 56, No. 15, 08.08.2013, p. 6259-6272.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Optimization of N-benzoylindazole derivatives as inhibitors of human neutrophil elastase
AU - Crocetti, Letizia
AU - Schepetkin, Igor A.
AU - Cilibrizzi, Agostino
AU - Graziano, Alessia
AU - Vergelli, Claudia
AU - Giomi, Donatella
AU - Khlebnikov, Andrey Ivanovich
AU - Quinn, Mark T.
AU - Giovannoni, Maria Paola
PY - 2013/8/8
Y1 - 2013/8/8
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84881450780&partnerID=8YFLogxK
U2 - 10.1021/jm400742j
DO - 10.1021/jm400742j
M3 - Article
VL - 56
SP - 6259
EP - 6272
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -