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References listed in PDB file
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Key reference
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Title
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Macrocyclic inhibitors of factor xia: discovery of alkyl-Substituted macrocyclic amide linkers with improved potency.
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Authors
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J.R.Corte,
W.Yang,
T.Fang,
Y.Wang,
H.Osuna,
A.Lai,
W.R.Ewing,
K.A.Rossi,
J.E.Myers,
S.Sheriff,
Z.Lou,
J.J.Zheng,
T.W.Harper,
J.M.Bozarth,
Y.Wu,
J.M.Luettgen,
D.A.Seiffert,
M.L.Quan,
R.R.Wexler,
P.Y.S.Lam.
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Ref.
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Bioorg Med Chem Lett, 2017,
27,
3833-3839.
[DOI no: ]
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PubMed id
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Abstract
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Optimization of macrocyclic inhibitors of FXIa is described which focused on
modifications to both the macrocyclic linker and the P1 group. Increases in
potency were discovered through interactions with a key hydrophobic region near
the S1 prime pocket by substitution of the macrocyclic linker with small alkyl
groups. Both the position of substitution and the absolute stereochemistry of
the alkyl groups on the macrocyclic linker which led to improved potency varied
depending on the ring size of the macrocycle. Replacement of the
chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the
polar surface area and improved the oral bioavailability for the series, albeit
at the cost of a decrease in potency.
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Secondary reference #1
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Title
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Tetrahydroquinoline derivatives as potent and selective factor xia inhibitors.
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Authors
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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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Ref.
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J Med Chem, 2014,
57,
955-969.
[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 of coagulation factor xia with in vivo antithrombotic activity.
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Authors
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J.J.Hangeland,
T.J.Friends,
K.A.Rossi,
J.M.Smallheer,
C.Wang,
Z.Sun,
J.R.Corte,
T.Fang,
P.C.Wong,
A.R.Rendina,
F.A.Barbera,
J.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.Quan.
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Ref.
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J Med Chem, 2014,
57,
9915-9932.
[DOI no: ]
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PubMed id
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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.Rendina,
J.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.Quan.
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Ref.
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Bioorg Med Chem Lett, 2015,
25,
925-930.
[DOI no: ]
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PubMed id
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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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Secondary reference #5
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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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Secondary reference #6
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Title
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Novel phenylalanine derived diamides as factor xia inhibitors.
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Authors
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L.M.Smith,
M.J.Orwat,
Z.Hu,
W.Han,
C.Wang,
K.A.Rossi,
P.J.Gilligan,
K.B.Pabbisetty,
H.Osuna,
J.R.Corte,
A.R.Rendina,
J.M.Luettgen,
P.C.Wong,
R.Narayanan,
T.W.Harper,
J.M.Bozarth,
E.J.Crain,
A.Wei,
V.Ramamurthy,
P.E.Morin,
B.Xin,
J.Zheng,
D.A.Seiffert,
M.L.Quan,
P.Y.Lam,
R.R.Wexler,
D.J.Pinto.
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Ref.
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Bioorg Med Chem Lett, 2016,
26,
472-478.
[DOI no: ]
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PubMed id
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Secondary reference #7
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Title
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Orally bioavailable pyridine and pyrimidine-Based factor xia inhibitors: discovery of the methyl n-Phenyl carbamate p2 prime group.
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Authors
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J.R.Corte,
T.Fang,
D.J.Pinto,
M.J.Orwat,
A.R.Rendina,
J.M.Luettgen,
K.A.Rossi,
A.Wei,
V.Ramamurthy,
J.E.Myers,
S.Sheriff,
R.Narayanan,
T.W.Harper,
J.J.Zheng,
Y.X.Li,
D.A.Seiffert,
R.R.Wexler,
M.L.Quan.
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Ref.
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Bioorg Med Chem Lett, 2016,
24,
2257-2272.
[DOI no: ]
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PubMed id
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Secondary reference #8
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Title
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Structure-Based design of macrocyclic factor xia inhibitors: discovery of the macrocyclic amide linker.
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Authors
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J.R.Corte,
T.Fang,
H.Osuna,
D.J.Pinto,
K.A.Rossi,
J.E.Myers,
S.Sheriff,
Z.Lou,
J.J.Zheng,
T.W.Harper,
J.M.Bozarth,
Y.Wu,
J.M.Luettgen,
D.A.Seiffert,
C.P.Decicco,
R.R.Wexler,
M.L.Quan.
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Ref.
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J Med Chem, 2017,
60,
1060-1075.
[DOI no: ]
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PubMed id
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