CHEMICAL, BIOCHEMICAL, PHARMACOKINETIC, AND BIOLOGICAL PROPERTIES OF L-680,833 - A POTENT, ORALLY-ACTIVE MONOCYCLIC BETA-LACTAM INHIBITOR OF HUMAN POLYMORPHONUCLEAR LEUKOCYTE ELASTASE

A series of potent and highly selective time-dependent monocyclic beta-lactam inhibitors of human polymorphonuclear leukocyte elastase (PMNE, EC 3.4.21.37) is described. The intrinsic potency of these compounds, as exemplified by L-680,833 (k(inactivation)/K(i) of 622,000 M-1-s-1), is reflected at the cellular level where it inhibits generation of the specific N-terminal cleavage product Aalpha-(1-21) from the Aalpha chain of fibrinogen by enzyme released from isolated polymorphonuclear leukocytes stimulated with fMet-Leu-Phe with an IC50 of 0.06 muM. The inhibitory activity of L-680,833 is also apparent in whole blood stimulated with A23187, where it inhibits formation of Aalpha-(1-21) and PMNE-alpha1-proteinase inhibitor complex formation with IC50 values of 9 muM. Pharmacokinetic studies indicate that after oral dosing L-680,833 is bioavailable in rats and rhesus monkeys. This oral bioavailability is reflected by the inhibition (i) of tissue damage elicited in hamster lungs by intratracheal instillation of human PMNE and (ii) enzyme released from human PMN stimulated after their transfer into the pleural cavity of mice. The properties of L-680,833 allow it to effectively supplement the activity of natural inhibitors of PMNE in vivo, suggesting that this type of low-molecular-weight synthetic inhibitor could have therapeutic value in diseases where PMNE damages tissue.