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References listed in PDB file
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Key reference
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Title
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Potent, Orally bioavailable, And efficacious macrocyclic inhibitors of factor xia. Discovery of pyridine-Based macrocycles possessing phenylazole carboxamide p1 groups.
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Authors
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J.R.Corte,
D.J.P.Pinto,
T.Fang,
H.Osuna,
W.Yang,
Y.Wang,
A.Lai,
C.G.Clark,
J.H.Sun,
R.Rampulla,
A.Mathur,
M.Kaspady,
P.R.Neithnadka,
Y.C.Li,
K.A.Rossi,
J.E.Myers,
S.Sheriff,
Z.Lou,
T.W.Harper,
C.Huang,
J.J.Zheng,
J.M.Bozarth,
Y.Wu,
P.C.Wong,
E.J.Crain,
D.A.Seiffert,
J.M.Luettgen,
P.Y.S.Lam,
R.R.Wexler,
W.R.Ewing.
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Ref.
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J Med Chem, 2020,
63,
784-803.
[DOI no: ]
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PubMed id
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Abstract
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Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show
excellent efficacy in preclinical thrombosis models with minimal effects on
hemostasis. The discovery of potent and selective FXIa inhibitors which are also
orally bioavailable has been a challenge. Here, we describe optimization of the
imidazole-based macrocyclic series and our initial progress toward meeting this
challenge. A two-pronged strategy, which focused on replacement of the imidazole
scaffold and the design of new P1 groups, led to the discovery of potent, orally
bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover,
pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide
P1, exhibited excellent selectivity against relevant blood coagulation enzymes
and displayed antithrombotic efficacy in a rabbit thrombosis model.
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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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Secondary reference #11
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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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Secondary reference #12
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Title
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Structure based design of macrocyclic factor xia inhibitors: discovery of cyclic p1 linker moieties with improved oral bioavailability.
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Authors
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C.G.Clark,
K.A.Rossi,
J.R.Corte,
T.Fang,
J.M.Smallheer,
I.De lucca,
D.S.Nirschl,
M.J.Orwat,
D.J.P.Pinto,
Z.Hu,
Y.Wang,
W.Yang,
Y.Jeon,
W.R.Ewing,
J.E.Myers,
S.Sheriff,
Z.Lou,
J.M.Bozarth,
Y.Wu,
A.Rendina,
T.Harper,
J.Zheng,
B.Xin,
Q.Xiang,
J.M.Luettgen,
D.A.Seiffert,
R.R.Wexler,
P.Y.S.Lam.
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Ref.
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Bioorg Med Chem Lett, 2019,
29,
126604.
[DOI no: ]
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PubMed id
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Secondary reference #13
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Title
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Orally bioavailable amine-Linked macrocyclic inhibitors of factor xia.
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Authors
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T.Fang,
J.R.Corte,
P.J.Gilligan,
Y.Jeon,
H.Osuna,
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,
R.R.Wexler,
P.Y.S.Lam.
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Ref.
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Bioorg Med Chem Lett, 2020,
30,
126949.
[DOI no: ]
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PubMed id
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