TY - JOUR
T1 - Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors
AU - Cantini, Niccolò
AU - Khlebnikov, Andrei I.
AU - Crocetti, Letizia
AU - Schepetkin, Igor A.
AU - Floresta, Giuseppe
AU - Guerrini, Gabriella
AU - Vergelli, Claudia
AU - Bartolucci, Gianluca
AU - Quinn, Mark T.
AU - Giovannoni, Maria Paola
N1 - Funding Information:
This research was supported in part by National Institutes of Health IDeA Program Grants GM110732, GM115371, and GM103474; USDA National Institute of Food and Agriculture Hatch project 1009546; the Montana State University Agricultural Experiment Station; the Tomsk Polytechnic University Competitiveness Enhancement Program (project CEP-SAMT-208/2020); and the Program of Increasing the Competitiveness of TSU (project No. 8.2.10.2018).
Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10–50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.
AB - Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10–50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.
KW - ADMET
KW - Human neutrophil elastase
KW - Inhibitors
KW - Molecular docking
KW - Nitrogen heterocycle
KW - Stability
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U2 - 10.1016/j.bmc.2020.115836
DO - 10.1016/j.bmc.2020.115836
M3 - Article
C2 - 33218895
AN - SCOPUS:85096428624
VL - 29
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
M1 - 115836
ER -