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

Jalmira Mulchande, Rita C. Guedes, Wing Yin Tsang, Michael I. Page, Rui Moreira, Jim Iley

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1783-1790
Number of pages8
JournalJournal of Medicinal Chemistry
Volume51
Issue number6
Early online date22 Feb 2008
DOIs
Publication statusPublished - 2008

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Lactams
Pancreatic Elastase
Acylation
Enzymes
Swine
Enzyme Inhibitors
Serine
Catalytic Domain
Hydrolysis
Electrons
azetidine

Cite this

Mulchande, J., Guedes, R. C., Tsang, W. Y., Page, M. I., Moreira, R., & Iley, J. (2008). Azetidine-2,4-diones (4-oxo-β-lactams) as Scaffolds for Designing Elastase Inhibitors. Journal of Medicinal Chemistry, 51(6), 1783-1790. https://doi.org/10.1021/jm701257h
Mulchande, Jalmira ; Guedes, Rita C. ; Tsang, Wing Yin ; Page, Michael I. ; Moreira, Rui ; Iley, Jim. / Azetidine-2,4-diones (4-oxo-β-lactams) as Scaffolds for Designing Elastase Inhibitors. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 6. pp. 1783-1790.
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Mulchande, J, Guedes, RC, Tsang, WY, Page, MI, Moreira, R & Iley, J 2008, 'Azetidine-2,4-diones (4-oxo-β-lactams) as Scaffolds for Designing Elastase Inhibitors', Journal of Medicinal Chemistry, vol. 51, no. 6, pp. 1783-1790. https://doi.org/10.1021/jm701257h

Azetidine-2,4-diones (4-oxo-β-lactams) as Scaffolds for Designing Elastase Inhibitors. / Mulchande, Jalmira; Guedes, Rita C.; Tsang, Wing Yin; Page, Michael I.; Moreira, Rui; Iley, Jim.

In: Journal of Medicinal Chemistry, Vol. 51, No. 6, 2008, p. 1783-1790.

Research output: Contribution to journalArticle

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AU - Mulchande, Jalmira

AU - Guedes, Rita C.

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AU - Iley, Jim

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AB - 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.

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