title: Pharmacological profile of the substituted beta-lactam L-659,286: a member of a new class of human PMN elastase inhibitors.
abstract: Human polymorphonuclear leukocyte elastase (PMN elastase) is inhibited by L-659,286 (7 alpha-methoxy-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4- triaz-in-3-yl)thio]methyl]-5-thia-1-aza-6R-bicyclo[4.2.O]oct-2-ene -2- pyrrolidine carboxamide-5,-dioxide) with a Ki of 0.4 microM. This inhibition is time-dependent, rapid, and only slowly reversible, with a t1/2 of greater than 3 days at 25 degrees C. L-659,286 is also highly selective for PMN elastase, as it does not inhibit thrombin, trypsin, papain, plasmin, chymotrypsin, or cathepsin G. L-659,286 administered intratracheally inhibits lung damage caused by administration via the same route of human PMN elastase into hamsters. In marmosets, L-659,286 is cleared from blood very rapidly after an intravenous injection but is recovered in bronchoalveolar lavage fluid for several hours after intratracheal administration.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bonney
authors.forename: B
authors.initials: B
authors.lastname: Ashe
authors.forename: A
authors.initials: A
authors.lastname: Maycock
authors.forename: P
authors.initials: P
authors.lastname: Dellea
authors.forename: K
authors.initials: K
authors.lastname: Hand
authors.forename: D
authors.initials: D
authors.lastname: Osinga
authors.forename: D
authors.initials: D
authors.lastname: Fletcher
authors.forename: R
authors.initials: R
authors.lastname: Mumford
authors.forename: P
authors.initials: P
authors.lastname: Davies
authors.forename: D
authors.initials: D
authors.lastname: Frankenfield
mesh_terms: D000818:Animals; D002143:Callitrichinae; D002511:Cephalosporins / Q000494:pharmacology*; D006224:Cricetinae; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000009:adverse effects / Q000037:antagonists & inhibitors*
chemical_list: D002511:Cephalosporins; C059583:L 659286; D010196:Pancreatic Elastase