 |
|
Title
|
|
Nonpeptidic inhibitors of human leukocyte elastase. 2. Design, synthesis, and in vitro activity of a series of 3-amino-6-arylopyridin-2-one trifluoromethyl ketones.
|
|
|
Authors
|
|
J.R.Damewood,
P.D.Edwards,
S.Feeney,
B.C.Gomes,
G.B.Steelman,
P.A.Tuthill,
J.C.Williams,
P.Warner,
S.A.Woolson,
D.J.Wolanin.
|
|
|
Ref.
|
|
J Med Chem, 1994,
37,
3303-3312.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
A series of potent nonpeptidic inhibitors of the enzyme human leukocyte elastase
(HLE) is reported. These inhibitors contain a 3-amino-2-pyridone ring as a
central template in which the pyridone carbonyl and 3-position NH group are
thought to form important hydrogen bonding interactions with the Val-216 residue
of HLE. Substitution of the 6-position of the pyridone ring by various alkyl and
aryl groups was found to afford increases in the in vitro potency of these
inhibitors. A 6-position phenyl group, compound 10f, was found to result in a
large increase in binding affinity, which was not obtained when the phenyl group
was placed in either the 4- or 5-position of the molecule. Compound 10f was
found to have good selectivity for HLE over other proteolytic enzymes, with the
exception of bovine pancreatic chymotrypsin (BPC). Substitution of the 6-phenyl
group in these molecules was found to decrease binding affinity for BPC without
adversely affecting affinity for HLE.
|
|
|
|