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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 parenteral small molecule coagulation factor xia inhibitor clinical candidate (bms-962212).
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Authors
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D.J.P.Pinto,
M.J.Orwat,
L.M.Smith,
M.L.Quan,
P.Y.S.Lam,
K.A.Rossi,
A.Apedo,
J.M.Bozarth,
Y.Wu,
J.J.Zheng,
B.Xin,
N.Toussaint,
P.Stetsko,
O.Gudmundsson,
B.Maxwell,
E.J.Crain,
P.C.Wong,
Z.Lou,
T.W.Harper,
S.A.Chacko,
J.E.Myers,
S.Sheriff,
H.Zhang,
X.Hou,
A.Mathur,
D.A.Seiffert,
R.R.Wexler,
J.M.Luettgen,
W.R.Ewing.
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Ref.
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J Med Chem, 2017,
60,
9703-9723.
[DOI no: ]
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PubMed id
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Abstract
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Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the
amplification of thrombin generation. Mounting evidence suggests that direct
inhibition of FXIa can block pathologic thrombus formation while preserving
normal hemostasis. Preclinical studies using a variety of approaches to reduce
FXIa activity, including direct inhibitors of FXIa, have demonstrated good
antithrombotic efficacy without increasing bleeding. On the basis of this
potential, we targeted our efforts at identifying potent inhibitors of FXIa with
a focus on discovering an acute antithrombotic agent for use in a hospital
setting. Herein we describe the discovery of a potent FXIa clinical candidate,
55 (FXIa Ki= 0.7 nM), with excellent preclinical efficacy in
thrombosis models and aqueous solubility suitable for intravenous
administration. BMS-962212 is a reversible, direct, and highly selective small
molecule inhibitor of FXIa.
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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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Secondary reference #9
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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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Secondary reference #10
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Title
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Macrocyclic factor xia inhibitors.
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Authors
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C.Wang,
J.R.Corte,
K.A.Rossi,
J.M.Bozarth,
Y.Wu,
S.Sheriff,
J.E.Myers,
J.M.Luettgen,
D.A.Seiffert,
R.R.Wexler,
M.L.Quan.
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Ref.
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Bioorg Med Chem Lett, 2017,
27,
4056-4060.
[DOI no: ]
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PubMed id
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