Azetidine-2,4-diones (4-Oxo-β-lactams) as Scaffolds for Designing Elastase Inhibitors

A new class of inhibitors 4-oxo-β-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-β-sultams. Inhibit...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1783-1790
Hauptverfasser: Mulchande, Jalmira, Guedes, Rita C, Tsang, Wing-Yin, Page, Michael I, Moreira, Rui, Iley, Jim
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:A new class of inhibitors 4-oxo-β-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-β-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl-N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett ρ-value of 0.65. Compared with a ρ-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of ∼5 × 105 M−1 s−1.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701257h