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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 (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.

SUBMITTER: Vergelli C

PROVIDER: S-EPMC5927774 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Vergelli Claudia C Schepetkin Igor A IA Crocetti Letizia L Iacovone Antonella A Giovannoni Maria Paola MP Guerrini Gabriella G Khlebnikov Andrei I AI Ciattini Samuele S Ciciani Giovanna G Quinn Mark T MT

Journal of enzyme inhibition and medicinal chemistry 20171201 1

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<sub>50</sub> value =20 nM) and chemical stability in aqueous buffer (t ...[more]

PMID: 28612630

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Project description:Human neutrophil elastase (HNE) is a serine protease that plays vital roles in inflammation, innate immune response, and tissue remodeling processes. HNE has been actively pursued as a drug target, particularly for the treatment of cardiopulmonary diseases. Although thousands of molecules have been reported to inhibit HNE, yet very few are being evaluated in early clinical trials, with sivelestat as the only approved HNE inhibitor. We report here a novel chemotype of sulfonated nonsaccharide heparin mimetics as potent and noncompetitive inhibitors of HNE. Using a chromogenic substrate hydrolysis assay, 14 sulfonated nonsaccharide heparin mimetics were tested for their inhibitory activity against HNE. Only 12 molecules inhibited HNE with IC50 values of 0.22-88.3 μM. The inhibition of HNE by these molecules was salt-dependent. Interestingly, a specific hexa-sulfonated molecule inhibited HNE with an IC50 value of 0.22 μM via noncompetitive mechanism, as demonstrated by Michaelis-Menten kinetics. The hexa-sulfonated derivative demonstrated at least 455-, 221-, 1590-, 21-, and 381-fold selectivity indices over other heparin-binding coagulation proteins including factors IIa, Xa, IXa, XIa, and FXIIIa, respectively. At the highest concentrations tested, the molecule also did not significantly inhibit other serine proteases of plasmin, trypsin, and chymotrypsin. Further supporting its selectivity, the molecule did not show heparin-like effects on clotting times of human plasma. The molecule also did not affect the proliferation of three cell lines at a concentration as high as 10 μM. Interestingly, the hexa-sulfonated molecule also inhibited cathepsin G with an IC50 value of 0.57 μM alluding to a dual anti-inflammatory action. A computational approach was exploited to identify putative binding site(s) for this novel class of HNE inhibitors. Overall, the reported hexa-sulfonated nonsaccharide heparin mimetic serves as a new platform to develop potent, selective, and noncompetitive inhibitors of HNE for therapeutic purposes.

Dataset Information

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

Publications

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

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