Azetidine-2,4-diones (4-oxo-beta-lactams) as scaffolds for designing elastase inhibitors

作者：Mulchande Jalmira; Guedes Rita C; Tsang Wing Yin; Page Michael I^*; Moreira Rui; Iley Jim

来源：Journal of Medicinal Chemistry, 2008, 51(6): 1783-1790.

DOI：10.1021/jm701257h

A new class of inhibitors 4-oxo-beta-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-beta-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 p-value of 0.65. Compared with a p-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 similar to 5 x 10(5) M(-1) s(-1).

• 出版日期2008-3-27