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Title
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Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones.
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Authors
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P.R.Bernstein,
D.Andisik,
P.K.Bradley,
C.B.Bryant,
C.Ceccarelli,
J.R.Damewood,
R.Earley,
P.D.Edwards,
S.Feeney,
B.C.Gomes.
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Ref.
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J Med Chem, 1994,
37,
3313-3326.
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PubMed id
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Abstract
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A series of nonpeptidic inhibitors of human leukocyte elastase (HLE) is
reported. These trifluoromethyl ketone-based inhibitors contain a
3-amino-6-phenylpyridone group as a central template. The effect of varying the
N-3 substituent in these inhibitors on in vitro potency, physical properties,
and oral activity in a hamster based, HLE-induced lung damage model is
described. The variety of substituents at this position that have little effect
on in vitro potency supports the idea that this region of the molecule does not
interact strongly with the enzyme. One exception to this generality is 13k,
which is substituted with a (4-acetamidophenyl)sulfonyl group. This compound has
a K(i) of 0.7 nM and is, in vitro, the most potent inhibitor in the series. In
contrast, variation of the N-3 substituent was found to have a dramatic effect
on activity after oral administration. Several analogs, including the parent
amine, 7, formamide, 2u, benzyl sulfamide, 13e, and benzyl sulfonamide, 13f,
show significant activity when administered at an oral dose of 2.5 mg/kg.
Support for the modeling-based design concepts was obtained through in vitro SAR
results and X-ray crystallographic analysis of the complex between 13d and
porcine pancreatic elastase (PPE), a closely related enzyme.
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