title: Azetidine-2,4-diones (4-oxo-beta-lactams) as scaffolds for designing elastase inhibitors.
abstract: 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 rho-value of 0.65. Compared with a rho-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 approximately 5 x 10 (5) M (-1) s (-1).
authors.affiliation: iMed UL, CECF, Faculdade de Farmácia, Universidade de Lisboa, Av. Forças Armadas, Lisbon, Portugal.
authors.forename: Jalmira
authors.initials: J
authors.lastname: Mulchande
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Wing-Yin
authors.initials: WY
authors.lastname: Tsang
authors.forename: Michael I
authors.initials: MI
authors.lastname: Page
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Jim
authors.initials: J
authors.lastname: Iley
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D001384:Azetidines; D004791:Enzyme Inhibitors; D010196:Pancreatic Elastase