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PDBsum entry 2q1j
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* Residue conservation analysis
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Enzyme class:
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Chains A, B:
E.C.3.4.21.6
- coagulation factor Xa.
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Reaction:
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Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.
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DOI no:
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Bioorg Med Chem Lett
14:4379-4392
(2006)
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PubMed id:
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The discovery of glycine and related amino acid-based factor Xa inhibitors.
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J.T.Kohrt,
K.J.Filipski,
W.L.Cody,
C.F.Bigge,
F.La,
K.Welch,
T.Dahring,
J.W.Bryant,
D.Leonard,
G.Bolton,
L.Narasimhan,
E.Zhang,
J.T.Peterson,
S.Haarer,
V.Sahasrabudhe,
N.Janiczek,
S.Desiraju,
M.Hena,
C.Fiakpui,
N.Saraswat,
R.Sharma,
S.Sun,
S.N.Maiti,
R.Leadley,
J.J.Edmunds.
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ABSTRACT
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Herein, we report on the identification of three potent glycine and related
amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl
pharmacophore. A X-ray crystal structure has shown that constrained glycine
derivatives with optimized N-substitution can greatly increase hydrophobic
interactions in the FXa active site. Also, the substitution of a pyridone ring
for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with
enhanced oral bioavailability.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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Y.K.Lee,
and
M.R.Player
(2011).
Developments in factor Xa inhibitors for the treatment of thromboembolic disorders.
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Med Res Rev,
31,
202-283.
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C.A.Van Huis,
C.F.Bigge,
A.Casimiro-Garcia,
W.L.Cody,
D.A.Dudley,
K.J.Filipski,
R.J.Heemstra,
J.T.Kohrt,
L.S.Narasimhan,
R.P.Schaum,
E.Zhang,
J.W.Bryant,
S.Haarer,
N.Janiczek,
R.J.Leadley,
T.McClanahan,
J.Thomas Peterson,
K.M.Welch,
and
J.J.Edmunds
(2007).
Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.
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Chem Biol Drug Des,
69,
444-450.
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PDB code:
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J.T.Kohrt,
C.F.Bigge,
J.W.Bryant,
A.Casimiro-Garcia,
L.Chi,
W.L.Cody,
T.Dahring,
D.A.Dudley,
K.J.Filipski,
S.Haarer,
R.Heemstra,
N.Janiczek,
L.Narasimhan,
T.McClanahan,
J.T.Peterson,
V.Sahasrabudhe,
R.Schaum,
C.A.Van Huis,
K.M.Welch,
E.Zhang,
R.J.Leadley,
and
J.J.Edmunds
(2007).
The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor.
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Chem Biol Drug Des,
70,
100-112.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
