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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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