title: Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase.
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 IC₅₀ 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.
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
authors: Letizia
authors: L
authors: Crocetti
authors: Maria Paola
authors: MP
authors: Giovannoni
authors: Igor A
authors: IA
authors: Schepetkin
authors: Mark T
authors: MT
authors: Quinn
authors: Andrei I
authors: AI
authors: Khlebnikov
authors: Agostino
authors: A
authors: Cilibrizzi
authors: Vittorio Dal
authors: VD
authors: Piaz
authors: Alessia
authors: A
authors: Graziano
authors: Claudia
authors: C
authors: Vergelli
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D019272:Leukocyte Elastase