58655-60-0Relevant academic research and scientific papers
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
, p. 1783 - 1790 (2008/09/21)
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.
