title: Synthesis, stability, biochemical and pharmacokinetic properties of a new potent and selective 4-oxo-β-lactam inhibitor of human leukocyte elastase.
abstract: The 4-oxo-β-lactams (azetidine-2,4-diones) are potent acylating agents of the human leukocyte elastase (HLE), a neutrophil serine protease that plays a key role in several inflammatory diseases. A novel 4-oxo-β-lactam containing a N-(4-(phenylsulphonylmethyl)phenyl) group, 3, was designed as a potential mechanism-based inhibitor capable of undergoing elimination of phenylsulphinate upon Ser-195 acylation. Compound 3 was found to be a potent slow-tight binding inhibitor of HLE, presenting a remarkable second-order rate constant of 1.46 x 10⁶ M⁻¹s⁻¹ and displaying selectivity over the proteinase 3 and cathepsin G. However, liberation of phenylsulphinate was not observed in the hydrolysis of 3 in both pH 7.4 phosphate buffer and human plasma. The C(max) values of 1207 μg/total blood, 179 μg/g spleen and 106 μg/g lung were determined by HPLC, following a single 30 mg/kg dose of 3 given intraperitoneally to NMRI mice, suggesting that the inhibitor distributes well into tissues. Although being a powerful selective inhibitor of HLE, 4-oxo-β-lactam 3 has a limited stability, being susceptible to off-target reactions (plasma and liver enzymes).
authors.affiliation: Medicinal Chemistry, iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, Lisbon, Portugal. jalmira@ff.ul.pt
authors.forename: Jalmira
authors.initials: J
authors.lastname: Mulchande
authors.forename: Sandra I
authors.initials: SI
authors.lastname: Simões
authors.forename: Maria M
authors.initials: MM
authors.lastname: Gaspar
authors.forename: Carla V
authors.initials: CV
authors.lastname: Eleutério
authors.forename: Rudi
authors.initials: R
authors.lastname: Oliveira
authors.forename: Maria E M
authors.initials: ME
authors.lastname: Cruz
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Jim
authors.initials: J
authors.lastname: Iley
mesh_terms: D000818:Animals; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007263:Infusions, Parenteral; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D004791:Enzyme Inhibitors; D047090:beta-Lactams; D019272:Leukocyte Elastase