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Doherty, James B.; Shah, Shrenik K.; Finke, Paul E.; Dorn,, Conrad P.; Hagmann, William K.; Hale, Jeffrey J.; Kissinger, Amy L.; Thompson, Kevan R.; Brause, karen; Chandler, Gilbert O.; Knight, Wilson B.; Maycock, Alan L.; Ashe, Bonnie M.; Weston, Hazel; Gale, Paul; Mumford, Richard A.; Andersen, O. Frederick; Williams, Hollis R.; Nolan, Thomas E.; Frankenfield, Dale L.; Underwood, Dennis; Vyas, Kamlesh P.; Kari, Prasad H.; Dahlgren, Mary E.; [...]

Chemical, Biochemical, Pharmacokinetic, and Biological Properties of L-680, 833: A Potent, Orally Active Monocyclic β-Lactam Inhibitor of Human Polymorphonuclear Leukocyte Elastase

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  • Medientyp: E-Artikel
  • Titel: Chemical, Biochemical, Pharmacokinetic, and Biological Properties of L-680, 833: A Potent, Orally Active Monocyclic β-Lactam Inhibitor of Human Polymorphonuclear Leukocyte Elastase
  • Beteiligte: Doherty, James B.; Shah, Shrenik K.; Finke, Paul E.; Dorn,, Conrad P.; Hagmann, William K.; Hale, Jeffrey J.; Kissinger, Amy L.; Thompson, Kevan R.; Brause, karen; Chandler, Gilbert O.; Knight, Wilson B.; Maycock, Alan L.; Ashe, Bonnie M.; Weston, Hazel; Gale, Paul; Mumford, Richard A.; Andersen, O. Frederick; Williams, Hollis R.; Nolan, Thomas E.; Frankenfield, Dale L.; Underwood, Dennis; Vyas, Kamlesh P.; Kari, Prasad H.; Dahlgren, Mary E.; [...]
  • Erschienen: National Academy of Sciences of the United States of America, 1993
  • Erschienen in: Proceedings of the National Academy of Sciences of the United States of America
  • Sprache: Englisch
  • ISSN: 0027-8424
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <p>A series of potent and highly selective time-dependent monocyclic β-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<sub>inactivation</sub>/K<sub>i</sub>of 622,000 M<sup>-1</sup>· s<sup>-1</sup>), is reflected at the cellular level where it inhibits generation of the specific N-terminal cleavage product Aα-(1-21) from the Aα chain of fibrinogen by enzyme released from isolated polymorphonuclear leukocytes stimulated with fMet-Leu-Phe with an IC<sub>50</sub>of 0.06 μM. The inhibitory activity of L-680,833 is also apparent in whole blood stimulated with A23187, where it inhibits formation of Aα-(1-21) and PMNE-α<sub>1</sub>-proteinase inhibitor complex formation with IC<sub>50</sub>values of 9 μM. 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.</p>
  • Zugangsstatus: Freier Zugang