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Title
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Specificity, stability, and potency of monocyclic beta-lactam inhibitors of human leucocyte elastase.
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Authors
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W.B.Knight,
B.G.Green,
R.M.Chabin,
P.Gale,
A.L.Maycock,
H.Weston,
D.W.Kuo,
W.M.Westler,
C.P.Dorn,
P.E.Finke.
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Ref.
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Biochemistry, 1992,
31,
8160-8170.
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PubMed id
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Abstract
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Stable, potent, highly specific, time-dependent monocyclic beta-lactam
inhibitors of human leucocyte elastase (HLE) are described. The heavily
substituted beta-lactams are stable under physiological conditions including in
the presence of enzymes of the digestive tract. The beta-lactams were unstable
in base. At pH 11.3 and 37 degrees C they were hydrolyzed with half-lives of
1.5-2 h. Hydrolysis produced characteristic products including the substituent
originally at C-4 of the lactam ring, a substituted urea, and products resulting
from decarboxylation of the acid after ring opening. The most potent beta-lactam
displayed only 2-fold less activity versus HLE than alpha 1PI, the natural
proteinaceous inhibitor. The compounds were more potent against the human and
primate PMN elastases than versus either the dog or rat enzymes. Differences in
the structure-activity relationships of the human versus the rat enzymes suggest
significant differences between these two functionally similar enzymes. The
specificity of these compounds toward HLE versus porcine pancreatic elastase
(PPE) is consistent with the differences in substrate specificity reported for
these enzymes [Zimmerman & Ashe (1977) Biochim. Biophys. Acta 480, 241-245].
These differences suggest that the alkyl substitutions at C-3 of the lactam ring
bind in the S1 specificity pocket of these enzymes. The dependence of the
stereochemistry at C-4 suggests additional differences between HLE and PPE. Most
of the compounds do not inhibit other esterases or human proteases. Weak,
time-dependent inhibition of human cathepsin G and alpha-chymotrypsin by one
compound suggested a binding mode to these enzymes that places the N-1
substitution in the S1 pocket.
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