Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors

Niccolò Cantini, Andrei I. Khlebnikov, Letizia Crocetti, Igor A. Schepetkin, Giuseppe Floresta, Gabriella Guerrini, Claudia Vergelli, Gianluca Bartolucci, Mark T. Quinn, Maria Paola Giovannoni

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number115836
JournalBioorganic and Medicinal Chemistry
Publication statusPublished - 1 Jan 2021


  • Human neutrophil elastase
  • Inhibitors
  • Molecular docking
  • Nitrogen heterocycle
  • Stability

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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