Abstract
Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC 50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.
| Original language | English |
|---|---|
| Pages (from-to) | 4460-4472 |
| Number of pages | 13 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 19 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 1 Aug 2011 |
| Externally published | Yes |
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Keywords
- 1-Benzoylindazoles
- Human neutrophil elastase
- Indazoles
- Inhibitors
- Structure-activity relationship
ASJC Scopus subject areas
- Pharmaceutical Science
- Drug Discovery
- Organic Chemistry
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
- Biochemistry
Cite this
Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase. / Crocetti, Letizia; Giovannoni, Maria Paola; Schepetkin, Igor A.; Quinn, Mark T.; Khlebnikov, Andrey Ivanovich; Cilibrizzi, Agostino; Piaz, Vittorio Dal; Graziano, Alessia; Vergelli, Claudia.
In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 15, 01.08.2011, p. 4460-4472.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase
AU - Crocetti, Letizia
AU - Giovannoni, Maria Paola
AU - Schepetkin, Igor A.
AU - Quinn, Mark T.
AU - Khlebnikov, Andrey Ivanovich
AU - Cilibrizzi, Agostino
AU - Piaz, Vittorio Dal
AU - Graziano, Alessia
AU - Vergelli, Claudia
PY - 2011/8/1
Y1 - 2011/8/1
N2 - Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC 50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.
AB - Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC 50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.
KW - 1-Benzoylindazoles
KW - Human neutrophil elastase
KW - Indazoles
KW - Inhibitors
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=79960558163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960558163&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.06.036
DO - 10.1016/j.bmc.2011.06.036
M3 - Article
C2 - 21741848
AN - SCOPUS:79960558163
VL - 19
SP - 4460
EP - 4472
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 15
ER -