Pharmacological profile of the substituted beta‐lactam L‐659,286: A member of a new class of human PMN elastase inhibitors

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Abstract
Human polymorphonuclear leukocyte elastase (PMN elastase) is inhibited by L‐659, 286 (7α‐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 μM. This inhibition is time‐dependent, rapid, and only slowly reversible, with a t1/2 of > 3 days at 25°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.