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PDBsum entry 4y76
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References listed in PDB file
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Key reference
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Title
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Factor xa inhibitors: s1 binding interactions of a series of n-{(3s)-1-[(1s)-1-Methyl-2-Morpholin-4-Yl-2-Oxoethyl]-2-Oxopyrrolidin-3-Yl}sulfonamides.
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Authors
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C.Chan,
A.D.Borthwick,
D.Brown,
C.L.Burns-Kurtis,
M.Campbell,
L.Chaudry,
C.W.Chung,
M.A.Convery,
J.N.Hamblin,
L.Johnstone,
H.A.Kelly,
S.Kleanthous,
A.Patikis,
C.Patel,
A.J.Pateman,
S.Senger,
G.P.Shah,
J.R.Toomey,
N.S.Watson,
H.E.Weston,
C.Whitworth,
R.J.Young,
P.Zhou.
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Ref.
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J Med Chem, 2007,
50,
1546-1557.
[DOI no: ]
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PubMed id
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Abstract
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Factor Xa inhibitory activities for a series of
N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides
with different P1 groups are described. These data provide insight into binding
interactions within the S1 primary specificity pocket; rationales are presented
for the derived SAR on the basis of electronic interactions through crystal
structures of fXa-ligand complexes and molecular modeling studies. A good
correlation between in vitro anticoagulant activities with lipophilicity and the
extent of human serum albumin binding is observed within this series of potent
fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with
selectivity over other trypsin-like serine proteases, identified 1f as a
candidate for further evaluation.
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