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 language | English |
|---|---|
| Pages (from-to) | 1783-1790 |
| Number of pages | 8 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 51 |
| Issue number | 6 |
| Early online date | 22 Feb 2008 |
| DOIs | |
| Publication status | Published - 2008 |
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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 journal › Article
TY - JOUR
T1 - Azetidine-2,4-diones (4-oxo-β-lactams) as Scaffolds for Designing Elastase Inhibitors
AU - Mulchande, Jalmira
AU - Guedes, Rita C.
AU - Tsang, Wing Yin
AU - Page, Michael I.
AU - Moreira, Rui
AU - Iley, Jim
PY - 2008
Y1 - 2008
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=41149169679&partnerID=8YFLogxK
U2 - 10.1021/jm701257h
DO - 10.1021/jm701257h
M3 - Article
VL - 51
SP - 1783
EP - 1790
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 6
ER -