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References listed in PDB file
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Key reference
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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.
[DOI no: ]
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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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Secondary reference #1
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Title
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Nonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, Intratracheally active, Pyridone-Based trifluoromethyl ketone.
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Authors
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P.R.Bernstein,
B.C.Gomes,
B.J.Kosmider,
E.P.Vacek,
J.C.Williams.
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Ref.
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J Med Chem, 1995,
38,
212-215.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Secondary reference #2
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Title
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Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, Synthesis, And X-Ray crystallography of a series of orally active 5-Aminopyrimidin-6-One-Containing trifluoromethyl ketones.
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Authors
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C.A.Veale,
P.R.Bernstein,
C.Bryant,
C.Ceccarelli,
J.R.Damewood,
R.Earley,
S.W.Feeney,
B.Gomes,
B.J.Kosmider,
G.B.Steelman.
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Ref.
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J Med Chem, 1995,
38,
98.
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
91%.
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Secondary reference #3
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Title
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Non-Peptidic inhibitors of human leukocyte elastase. 4. Design, Synthesis, And in vitro and in vivo activity of a series of beta-Carbolinone-Containing trifluoromethyl ketones.
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Authors
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C.A.Veale,
J.R.Damewood,
G.B.Steelman,
C.Bryant,
B.Gomes,
J.Williams.
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Ref.
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J Med Chem, 1995,
38,
86-97.
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
93%.
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Secondary reference #4
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Title
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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.
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Authors
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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.
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Ref.
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J Med Chem, 1994,
37,
3303-3312.
[DOI no: ]
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PubMed id
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Secondary reference #5
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Title
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Non-Peptidic inhibitors of human leukocyte elastase. 1. The design and synthesis of pyridone-Containing inhibitors.
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Authors
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P.Warner,
R.C.Green,
B.Gomes,
A.M.Strimpler.
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Ref.
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J Med Chem, 1994,
37,
3090-3099.
[DOI no: ]
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PubMed id
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Secondary reference #6
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Title
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Design of orally active, Non-Peptidic inhibitors of human leukocyte elastase.
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Authors
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F.J.Brown,
D.W.Andisik,
P.R.Bernstein,
C.B.Bryant,
C.Ceccarelli,
J.R.Damewood,
P.D.Edwards,
R.A.Earley,
S.Feeney,
R.C.Green.
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Ref.
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J Med Chem, 1994,
37,
1259-1261.
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PubMed id
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Secondary reference #7
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Title
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Design, Synthesis, And kinetic evaluation of a unique class of elastase inhibitors, The peptidyl alpha-Ketobenzoxazoles,And the x-Ray crystal structure of the covalent complex between porcine pancreatic elastase and ac-Ala-Pro-Val-2-Benzoxazole
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Authors
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P.D.Edwards,
E.F.Meyer,
J.Vijayalakshmi,
P.A.Tuthill,
D.A.Andisik,
B.Gomes,
A.Strimpler.
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Ref.
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j am chem soc, 1992,
114,
1854.
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Secondary reference #8
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Title
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Crystal structure of the covalent complex formed by a peptidyl alpha,Alpha-Difluoro-Beta-Keto amide with porcine pancreatic elastase at 1.78-Angstrom resolution
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Authors
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L.H.Takahashi,
R.Radhakrishnan,
R.E.Rosenfield,
E.F.Meyer,
D.A.Trainor.
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Ref.
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j am chem soc, 1989,
111,
3368.
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Secondary reference #9
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Title
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X-Ray diffraction analysis of the inhibition of porcine pancreatic elastase by a peptidyl trifluoromethylketone.
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Authors
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L.H.Takahashi,
R.Radhakrishnan,
R.E.Rosenfield,
E.F.Meyer,
D.A.Trainor,
M.Stein.
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Ref.
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J Mol Biol, 1988,
201,
423-428.
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PubMed id
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