Further modifications of 1H-pyrrolo[2,3-b]pyridine derivatives as inhibitors of human neutrophil elastase

Maria P. Giovannoni, Niccolò Cantini, Letizia Crocetti, Gabriella Guerrini, Antonella Iacovone, Igor A. Schepetkin, Claudia Vergelli, Andrei I. Khlebnikov, Mark T. Quinn

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes and is considered to be a multifunctional enzyme. HNE is also involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrrolo[2,3-b]pyridine derivatives of our previously reported potent HNE inhibitors. Our results show that position 2 of the pyrrolo[2,3-b]pyridine scaffold must be unsubstituted, and modifications of this position resulted in loss of HNE inhibitory activity. Conversely, the introduction of certain substituents at position 5 was tolerated, with retention of HNE inhibitory activity (IC 50 = 15–51 nM) after most substitutions, indicating that bulky and/or lipophilic substituents at position 5 probably interact with the large pocket of the enzyme site and allow Michaelis complex formation. The possibility of Michaelis complex formation between Ser195 and the ligand carbonyl group was assessed by molecular docking, and it was found that highly active HNE inhibitors are characterized by geometries favorable for Michaelis complex formation and by relatively short lengths of the proton transfer channel via the catalytic triad.

Original languageEnglish
JournalDrug Development Research
Publication statusPublished - 1 Jan 2019


  • human neutrophil elastase inhibitors
  • molecular docking
  • pyrrolo[2,3-b]pyridine

ASJC Scopus subject areas

  • Drug Discovery

Fingerprint Dive into the research topics of 'Further modifications of 1H-pyrrolo[2,3-b]pyridine derivatives as inhibitors of human neutrophil elastase'. Together they form a unique fingerprint.

Cite this