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Human leukocyte elastase (HLE) is a serine protease produced by neutrophils that has been implicated in diseases such as emphysema and cystic fibrosis. An HLE inhibitor may have therapeutic value in these diseases. An active site model of HLE bound to a tripeptidic trifluoromethyl ketone (TFMK) inhibitor, 2, was created from X-ray structures of HLE and porcine pancreatic elastase. Analysis of the model indicated a preferred binding conformation for the tripeptide and potentially important interactions between it and the enzyme. This information was used to aid in the design of a series of novel, pyridone-containing, non-peptidic HLE inhibitors such as 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo- 1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)ace tam ide (5b) (Ki = 280 +/- 78 nM). Inspection of the active site model suggested that a benzyl substituent at the 5-position of the pyridone ring might improve potency by forming a lipophilic interaction with the enzyme S2 pocket. Synthesis and biological evaluation of a series of 5-benzylpyridone TFMKs provided evidence for this proposition. Further analysis of the model indicated that substitution on the 3-amino group of the pyridone ring with a hydrogen bond acceptor could potentially lead to interactions with the NH atoms of glycine-218 and/or -219. The oxalate derivative 2-[5-benzyl- 3-(carboxycarbonyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifl uor o-1- isopropyl-2-oxopropyl)acetamide (5v) was synthesized and found to have a Ki of 48 +/- 9 nM. Unfortunately, none of the compounds tested was active in an in vivo model of HLE-induced lung injury when dosed orally.

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