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Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors

Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inh...

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Detalles Bibliográficos
Autores principales: Vergelli, Claudia, Schepetkin, Igor A., Crocetti, Letizia, Iacovone, Antonella, Giovannoni, Maria Paola, Guerrini, Gabriella, Khlebnikov, Andrei I., Ciattini, Samuele, Ciciani, Giovanna, Quinn, Mark T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927774/
https://www.ncbi.nlm.nih.gov/pubmed/28612630
http://dx.doi.org/10.1080/14756366.2017.1326915
Descripción
Sumario:Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure–activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC(50) value =20 nM) and chemical stability in aqueous buffer (t(1/2)=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups.