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

Abstract:

: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 (IC50 value =20 nM) and chemical stability in aqueous buffer (t1/2=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.

authors

Vergelli C,Schepetkin IA,Crocetti L,Iacovone A,Giovannoni MP,Guerrini G,Khlebnikov AI,Ciattini S,Ciciani G,Quinn MT

doi

10.1080/14756366.2017.1326915

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

821-831

issue

1

eissn

1475-6366

issn

1475-6374

journal_volume

32

pub_type

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