|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase
|
|
|
Title:
|
|
Factor xa in complex with the inhibitor apixaban (bms-562247) aka 1- (4-methoxyphenyl)-7-oxo-6-(4-(2-oxo-1-piperidinyl)phenyl)-4,5,6,7- tetrahydro-1h-pyrazolo[3, 4-c]pyridine-3-carboxamide
|
|
Structure:
|
|
Coagulation factor x (ec 3.4.21.6) (stuart factor) (stuart- prower factor). Chain: a. Fragment: coagulation factor x, heavy chain. Synonym: factor xa heavy chain, activated factor xa heavy chain. Coagulation factor x (ec 3.4.21.6) (stuart factor) (stuart- prower factor). Chain: l. Fragment: coagulation factor x, light chain.
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Other_details: proteolytic cleavage product
|
|
Resolution:
|
|
|
2.30Å
|
R-factor:
|
0.232
|
R-free:
|
0.277
|
|
|
Authors:
|
|
R.Alexander
|
|
Key ref:
|
|
D.J.Pinto
et al.
(2007).
Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.
J Med Chem,
50,
5339-5356.
PubMed id:
|
|
|
Date:
|
|
|
02-Mar-07
|
Release date:
|
16-Oct-07
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
Chains A, L:
E.C.3.4.21.6
- coagulation factor Xa.
|
|
|
|
|
|
|
Reaction:
|
|
Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
J Med Chem
50:5339-5356
(2007)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.
|
|
D.J.Pinto,
M.J.Orwat,
S.Koch,
K.A.Rossi,
R.S.Alexander,
A.Smallwood,
P.C.Wong,
A.R.Rendina,
J.M.Luettgen,
R.M.Knabb,
K.He,
B.Xin,
R.R.Wexler,
P.Y.Lam.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Efforts to identify a suitable follow-on compound to razaxaban (compound 4)
focused on modification of the carboxamido linker to eliminate potential in vivo
hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the
novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa
binding activity. Exceptional potency of the series prompted an investigation of
the neutral P1 moieties that resulted in the identification of the
p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral
bioavailability. Further optimization of the C-3 pyrazole position and
replacement of the terminal P4 ring with a neutral heterocycle culminated in the
discovery of
1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
(apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency,
selectivity, and efficacy and has an improved pharmacokinetic profile relative
to 4.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
E.Perzborn,
S.Roehrig,
A.Straub,
D.Kubitza,
and
F.Misselwitz
(2011).
The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor.
|
| |
Nat Rev Drug Discov,
10,
61-75.
|
|
|
|
|
|
|
K.Borensztajn,
and
C.A.Spek
(2011).
Blood coagulation factor Xa as an emerging drug target.
|
| |
Expert Opin Ther Targets,
15,
341-349.
|
|
|
|
|
|
|
M.A.Giorgi,
H.Cohen Arazi,
C.D.Gonzalez,
and
G.Di Girolamo
(2011).
Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban.
|
| |
Expert Opin Pharmacother,
12,
567-577.
|
|
|
|
|
|
|
P.C.Wong,
D.J.Pinto,
and
D.Zhang
(2011).
Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor.
|
| |
J Thromb Thrombolysis,
31,
478-492.
|
|
|
|
|
|
|
Y.K.Lee,
and
M.R.Player
(2011).
Developments in factor Xa inhibitors for the treatment of thromboembolic disorders.
|
| |
Med Res Rev,
31,
202-283.
|
|
|
|
|
|
|
C.Altuğ,
Y.Dürüst,
M.C.Elliott,
B.M.Kariuki,
T.Rorstad,
and
M.Zaal
(2010).
Reaction of heterocyclic enamines with nitrile oxide and nitrilimine precursors.
|
| |
Org Biomol Chem,
8,
4978-4986.
|
|
|
|
|
|
|
C.Roser-Jones,
and
R.C.Becker
(2010).
Apixaban: an emerging oral factor Xa inhibitor.
|
| |
J Thromb Thrombolysis,
29,
141-146.
|
|
|
|
|
|
|
D.Garcia,
E.Libby,
and
M.A.Crowther
(2010).
The new oral anticoagulants.
|
| |
Blood,
115,
15-20.
|
|
|
|
|
|
|
D.Zhang,
K.He,
N.Raghavan,
L.Wang,
E.J.Crain,
B.He,
B.Xin,
J.M.Luettgen,
and
P.C.Wong
(2010).
Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits.
|
| |
J Thromb Thrombolysis,
29,
70-80.
|
|
|
|
|
|
|
H.J.Rupprecht,
and
R.Blank
(2010).
Clinical pharmacology of direct and indirect factor Xa inhibitors.
|
| |
Drugs,
70,
2153-2170.
|
|
|
|
|
|
|
J.P.Piccini,
R.D.Lopes,
and
K.W.Mahaffey
(2010).
Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation.
|
| |
Curr Opin Cardiol,
25,
312-320.
|
|
|
|
|
|
|
R.S.Mehta
(2010).
Novel oral anticoagulants for prophylaxis and treatment of venous thromboembolism: part I (Factor Xa inhibitors).
|
| |
Expert Rev Hematol,
3,
227-241.
|
|
|
|
|
|
|
S.Kopp,
R.Baur,
E.Sigel,
H.Möhler,
and
K.H.Altmann
(2010).
Highly potent modulation of GABA(A) receptors by valerenic acid derivatives.
|
| |
ChemMedChem,
5,
678-681.
|
|
|
|
|
|
|
L.Armaganijan,
J.Eikelboom,
J.S.Healey,
and
C.A.Morillo
(2009).
New pharmacotherapy for stroke prevention in atrial fibrillation: Update 2010.
|
| |
Adv Ther,
26,
1058-1071.
|
|
|
|
|
|
|
P.C.Wong,
E.J.Crain,
C.A.Watson,
and
B.Xin
(2009).
Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits.
|
| |
J Thromb Haemost,
7,
1313-1320.
|
|
|
|
|
|
|
J.Carreiro,
and
J.Ansell
(2008).
Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict.
|
| |
Expert Opin Investig Drugs,
17,
1937-1945.
|
|
|
|
|
|
|
M.H.Umer Usman,
S.Raza,
S.Raza,
and
M.Ezekowitz
(2008).
Advancement in antithrombotics for stroke prevention in atrial fibrillation.
|
| |
J Interv Card Electrophysiol,
22,
129-137.
|
|
|
|
|
|
|
M.H.Usman,
L.A.Notaro,
H.Patel,
and
M.D.Ezekowitz
(2008).
New developments in anticoagulation for atrial fibrillation.
|
| |
Curr Treat Options Cardiovasc Med,
10,
388-397.
|
|
|
|
|
|
|
P.C.Wong,
C.A.Watson,
and
E.J.Crain
(2008).
Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits.
|
| |
J Thromb Haemost,
6,
1736-1741.
|
|
|
|
|
|
|
P.C.Wong,
E.J.Crain,
B.Xin,
R.R.Wexler,
P.Y.Lam,
D.J.Pinto,
J.M.Luettgen,
and
R.M.Knabb
(2008).
Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies.
|
| |
J Thromb Haemost,
6,
820-829.
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
|
 |
Links
