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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Factor xa in complex with bay59-7939
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Structure:
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Activated factor xa heavy chain. Chain: a. Fragment: residues 235-468. Synonym: factor xa, stuart factor, stuart-prower factor. Activated factor xa heavy chain. Chain: b. Fragment: residues 129-177. Synonym: factor xa, stuart factor, stuart-prower factor
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606
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Resolution:
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2.08Å
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R-factor:
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0.220
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R-free:
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0.259
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Authors:
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S.Roehrig,A.Straub,J.Pohlmann,T.Lampe,J.Pernerstorfer,K.Schlemmer, P.Reinemer,E.Perzborn,M.Schaefer
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Key ref:
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S.Roehrig
et al.
(2005).
Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor.
J Med Chem,
48,
5900-5908.
PubMed id:
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Date:
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24-Oct-08
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Release date:
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11-Nov-08
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PROCHECK
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Headers
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References
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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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J Med Chem
48:5900-5908
(2005)
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PubMed id:
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Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor.
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S.Roehrig,
A.Straub,
J.Pohlmann,
T.Lampe,
J.Pernerstorfer,
K.H.Schlemmer,
P.Reinemer,
E.Perzborn.
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ABSTRACT
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Despite recent progress in antithrombotic therapy, there is still an unmet
medical need for safe and orally available anticoagulants. The coagulation
enzyme Factor Xa (FXa) is a particularly promising target, and recent efforts in
this field have focused on the identification of small-molecule inhibitors with
good oral bioavailability. We identified oxazolidinone derivatives as a new
class of potent FXa inhibitors. Lead optimization led to the discovery of BAY
59-7939 (5), a highly potent and selective, direct FXa inhibitor with excellent
in vivo antithrombotic activity. The X-ray crystal structure of 5 in complex
with human FXa clarified the binding mode and the stringent requirements for
high affinity. The interaction of the neutral ligand chlorothiophene in the S1
subsite allows for the combination of good oral bioavailability and high potency
for nonbasic 5. Compound 5 is currently under clinical development for the
prevention and treatment of thromboembolic diseases.
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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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E.Perzborn,
S.Roehrig,
A.Straub,
D.Kubitza,
and
F.Misselwitz
(2011).
The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor.
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Nat Rev Drug Discov,
10,
61-75.
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F.Misselwitz,
S.D.Berkowitz,
and
E.Perzborn
(2011).
The discovery and development of rivaroxaban.
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Ann N Y Acad Sci,
1222,
64-75.
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H.G.Wallnoefer,
K.R.Liedl,
and
T.Fox
(2011).
A challenging system: free energy prediction for factor Xa.
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J Comput Chem,
32,
1743-1752.
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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.Bissantz,
B.Kuhn,
and
M.Stahl
(2010).
A medicinal chemist's guide to molecular interactions.
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J Med Chem,
53,
5061-5084.
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E.Lindhoff-Last,
M.M.Samama,
T.L.Ortel,
J.I.Weitz,
and
T.E.Spiro
(2010).
Assays for measuring rivaroxaban: their suitability and limitations.
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Ther Drug Monit,
32,
673-679.
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H.G.Wallnoefer,
T.Fox,
K.R.Liedl,
and
C.S.Tautermann
(2010).
Dispersion dominated halogen-π interactions: energies and locations of minima.
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Phys Chem Chem Phys,
12,
14941-14949.
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J.P.Piccini,
R.D.Lopes,
and
K.W.Mahaffey
(2010).
Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation.
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Curr Opin Cardiol,
25,
312-320.
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S.T.Duggan,
L.J.Scott,
and
G.L.Plosker
(2009).
Rivaroxaban: a review of its use for the prevention of venous thromboembolism after total hip or knee replacement surgery.
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Drugs,
69,
1829-1851.
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T.Chen,
and
S.Lam
(2009).
Rivaroxaban: an oral direct factor xa inhibitor for the prevention of thromboembolism.
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Cardiol Rev,
17,
192-197.
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C.Krishnasamy,
A.Raghuraman,
L.B.Kier,
and
U.R.Desai
(2008).
Application of molecular connectivity and electro-topological indices in quantitative structure-activity analysis of pyrazole derivatives as inhibitors of factor xa and thrombin.
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Chem Biodivers,
5,
2609-2620.
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J.P.Piccini,
M.R.Patel,
K.W.Mahaffey,
K.A.Fox,
and
R.M.Califf
(2008).
Rivaroxaban, an oral direct factor Xa inhibitor.
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Expert Opin Investig Drugs,
17,
925-937.
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M.R.Lassen,
and
V.Laux
(2008).
Emergence of new oral antithrombotics: a critical appraisal of their clinical potential.
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Vasc Health Risk Manag,
4,
1373-1386.
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Y.Imaeda,
T.Miyawaki,
H.Sakamoto,
F.Itoh,
N.Konishi,
K.Hiroe,
M.Kawamura,
T.Tanaka,
and
K.Kubo
(2008).
Discovery of sulfonylalkylamides: A new class of orally active factor Xa inhibitors.
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Bioorg Med Chem,
16,
2243-2260.
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Y.N.Imai,
Y.Inoue,
I.Nakanishi,
and
K.Kitaura
(2008).
Cl-pi interactions in protein-ligand complexes.
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Protein Sci,
17,
1129-1137.
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A.Stürzebecher,
D.Dönnecke,
A.Schweinitz,
O.Schuster,
P.Steinmetzer,
U.Stürzebecher,
J.Kotthaus,
B.Clement,
J.Stürzebecher,
and
T.Steinmetzer
(2007).
Highly potent and selective substrate analogue factor xa inhibitors containing d-homophenylalanine analogues as p3 residue: part 2.
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ChemMedChem,
2,
1043-1053.
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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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B.I.Eriksson,
and
D.J.Quinlan
(2006).
Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery.
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Drugs,
66,
1411-1429.
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M.Lobell,
M.Hendrix,
B.Hinzen,
J.Keldenich,
H.Meier,
C.Schmeck,
R.Schohe-Loop,
T.Wunberg,
and
A.Hillisch
(2006).
In silico ADMET traffic lights as a tool for the prioritization of HTS hits.
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ChemMedChem,
1,
1229-1236.
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T.Wunberg,
M.Hendrix,
A.Hillisch,
M.Lobell,
H.Meier,
C.Schmeck,
H.Wild,
and
B.Hinzen
(2006).
Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits.
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Drug Discov Today,
11,
175-180.
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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
