Pharmacological profile of the substituted beta-lactam L-659,286: a member of a new class of human PMN elastase inhibitors.
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.
Bonney
R J
RJ
Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Ashe
B
B
Maycock
A
A
Dellea
P
P
Hand
K
K
Osinga
D
D
Fletcher
D
D
Mumford
R
R
Davies
P
P
Frankenfield
D
D
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*
D002511:Cephalosporins; C059583:L 659286; D010196:Pancreatic Elastase