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PDBsum entry 4na7
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Hydrolase/hydrolase inhibitor
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PDB id
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4na7
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Factor xia in complex with the inhibitor 3'-[(2s,4r)-6-carbamimidoyl- 4-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl]-4-carbamoyl-5'- [(3-methylbutanoyl)amino]biphenyl-2-carboxylic acid
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Structure:
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Coagulation factor xi. Chain: a. Synonym: fxi, plasma thromboplastin antecedent, pta, coagulation factor xia heavy chain, coagulation factor xia light chain. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.80Å
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R-factor:
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0.241
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R-free:
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0.269
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Authors:
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A.Wei
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Key ref:
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M.L.Quan
et al.
(2014).
Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.
J Med Chem,
57,
955-969.
PubMed id:
DOI:
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Date:
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21-Oct-13
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Release date:
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12-Feb-14
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PROCHECK
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Headers
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References
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P03951
(FA11_HUMAN) -
Coagulation factor XI from Homo sapiens
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Seq:
Struc:
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625 a.a.
238 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.4.21.27
- coagulation factor XIa.
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Reaction:
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Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.
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DOI no:
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J Med Chem
57:955-969
(2014)
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PubMed id:
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Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.
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M.L.Quan,
P.C.Wong,
C.Wang,
F.Woerner,
J.M.Smallheer,
F.A.Barbera,
J.M.Bozarth,
R.L.Brown,
M.R.Harpel,
J.M.Luettgen,
P.E.Morin,
T.Peterson,
V.Ramamurthy,
A.R.Rendina,
K.A.Rossi,
C.A.Watson,
A.Wei,
G.Zhang,
D.Seiffert,
R.R.Wexler.
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ABSTRACT
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Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the
potential to demonstrate robust efficacy with a low bleeding risk profile.
Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa
inhibitors. Compound 1 was identified as a potent and selective tool compound
for proof of concept studies. It exhibited excellent antithrombotic efficacy in
rabbit thrombosis models and did not prolong bleeding times. This demonstrates
proof of concept for the FXIa mechanism in animal models with a reversible,
small molecule inhibitor.
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Links
