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References listed in PDB file
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Key reference
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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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Abstract
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A novel series of macrocyclic FXIa inhibitors was designed based on our lead
acyclic phenyl imidazole chemotype. Our initial macrocycles, which were
double-digit nanomolar FXIa inhibitors, were further optimized with assistance
from utilization of structure-based drug design and ligand bound X-ray crystal
structures. This effort resulted in the discovery of a macrocyclic amide linker
which was found to form a key hydrogen bond with the carbonyl of Leu41 in the
FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa
series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent
anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM)
and excellent selectivity against the relevant blood coagulation enzymes.
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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 ii,
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.Renj.M.Luettgen,
P.C.Wong,
R.Narayanan,
T.Harper,
J.M.Bozarte.J.Crain,
A.Wei,
V.Ramamurthy,
P.E.Morin,
D.A.Seiffert,
M.L.Quan,
P.Y.S.Lam,
R.R.Wexler,
D.J.P.Pinto.
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Ref.
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bioorg med chem lett, 2016,
26,
472.
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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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