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References listed in PDB file
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Key reference
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Title
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Discovery of a potent parenterally administered factor xia inhibitor with hydroxyquinolin-2(1h)-One as the p2' Moiety.
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Authors
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Z.Hu,
P.C.Wong,
P.J.Gilligan,
W.Han,
K.B.Pabbisetty,
J.M.Bozarth,
E.J.Crain,
T.Harper,
J.M.Luettgen,
J.E.Myers,
V.Ramamurthy,
K.A.Rossi,
S.Sheriff,
C.A.Watson,
A.Wei,
J.J.Zheng,
D.A.Seiffert,
R.R.Wexler,
M.L.Quan.
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Ref.
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Acs Med Chem Lett, 2015,
6,
590-595.
[DOI no: ]
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PubMed id
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Abstract
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Structure-activity relationship optimization of phenylalanine P1' and P2'
regions with a phenylimidazole core resulted in a series of potent FXIa
inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa
affinity and metabolic stability. Incorporation of an N-methyl piperazine amide
group to replace the phenylalanine improved both FXIa potency and aqueous
solubility. Combination of the optimization led to the discovery of FXIa
inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM.
Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model
with minimal bleeding time prolongation.
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Secondary reference #1
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Title
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Cloning, Purification, Crystallization and 1.57 å resolution X-Ray data analysis of amsi, The tyrosine phosphatase controlling amylovoran biosynthesis in the plant pathogen erwinia amylovora.
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Authors
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S.Benini,
L.Caputi,
M.Cianci.
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Ref.
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Acta Crystallogr F Struct Biol Commun, 2014,
70,
1693-1696.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Phenylimidazoles as potent and selective inhibitors o coagulation factor xia with in vivo antithrombotic ac
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Authors
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J.J.Hangeland,
T.J.Friends,
K.A.Rossi,
J.M.Smallheer,
C.Wz.Sun,
J.R.Corte,
T.Fang,
P.C.Wong,
A.R.Rendina,
F.A.Barbej.M.Bozarth,
J.M.Luettgen,
C.A.Watson,
G.Zhang,
A.Wei,
V.Ramamurthy,
P.E.Morin,
G.S.Bisacchi,
S.Subramaniam,
P.Arunachalam,
A.Mathur,
D.A.Seiffert,
R.R.Wexler,
M.L.Qu.
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Ref.
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j med chem, 2014,
57,
9915.
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Secondary reference #3
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Title
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Pyridine and pyridinone-Based factor xia inhibitors
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Authors
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J.R.Corte,
T.Fang,
J.J.Hangeland,
T.J.Friends,
A.R.Rendinj.M.Luettgen,
J.M.Bozarth,
F.A.Barbera,
K.A.Rossi,
A.Wei,
V.Ramamurthy,
P.E.Morin,
D.A.Seiffert,
R.R.Wexler,
M.L.Qu.
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Ref.
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bioorg med chem lett, 2015,
25,
925.
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Secondary reference #4
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Title
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Structure-Based design of inhibitors of coagulation factor xia with novel p1 moieties.
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Authors
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D.J.Pinto,
J.M.Smallheer,
J.R.Corte,
E.J.Austin,
C.Wang,
T.Fang,
L.M.Smith,
K.A.Rossi,
A.R.Rendina,
J.M.Bozarth,
G.Zhang,
A.Wei,
V.Ramamurthy,
S.Sheriff,
J.E.Myers,
P.E.Morin,
J.M.Luettgen,
D.A.Seiffert,
M.L.Quan,
R.R.Wexler.
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Ref.
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Bioorg Med Chem Lett, 2015,
25,
1635-1642.
[DOI no: ]
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PubMed id
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