Review
Novel factor Xa inhibitors:
a patent review
Modesto de Candia, Gianfranco Lopopolo & Cosimo Altomare†
†University
1.
Introduction
2.
Structure-based drug design
of small molecule factor Xa
inhibitors
3.
Therapeutic applications
4.
Survey of the patent literature
5.
Expert opinion
of Bari, Dipartimento Farmaco-Chimico, Via E. Orabona 4, I-70125 Bari, Italy
Importance of the field. New oral anticoagulants with favorable safety profiles
and fixed doses are required for the management of thromboembolism and
stroke prevention in patients with atrial fibrillation. Among them, fXa inhibitors (the so-called xabans) are attractive options that can overcome limitations
(e.g., bleeding) of the current oral antithrombotic therapy. The rational design
of small-molecule direct fXa inhibitors, whose importance is testified by the
growing number of publications and patents recently registered, has been
fully supported by the X-ray crystallography of enzyme–ligand complexes.
Areas covered in this review. Pubmed, SciFinder® Scholar, ISI web of knowledgeSM, http://ep.espacenet.com/ and Google websites were used as the main
sources for literature retrieving, and > 100 patents filed between 2006 and
April 2009, reviewed and discussed herein, highlight the variety among the
P1 and P4 moieties on suitable scaffolds.
What the reader will gain. The replacement of the benzamidine P1 moiety,
,
which characterizes the first generation, with less basic bioisosteric
ad or nonpolar
nlo
neutral P1 groups led to the disclosure of numerous fXa w
inhibitors
with high
o se.
d
u
potency, selectivity and oral bioavailability. Novel aselective
fXa
inhibitors
n
c nal
s
o
r
with stable pharmacokinetics, better therapeutic windows
and ease-of-use than
se pers
uadvanced
the existing anticoagulants are currently under
stage clinical trials.
d
r
e fo
y
ris Phase
Take-home message. Available data from
II
and
Phase III studies
p
o
th co
uas
e
A
l
reflect the drive towards fXa inhibitors
potentially
more
effective
and safer
.
g
ted a sin is expected to address two major
i
antithrombotic drugs. Their development
b
hi int
ro prsafety
needs for anticoagulation, namely
and ease-of-use, and to significantly
p
se and
affect the anticoagulantd umarket.
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ise ie
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Keywords: acute coronary
, anticoagulant, antithrombotic, factor Xa inhibitor,
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Expert Opin. Ther. Patents (2009) 19(11):1535-1580
1.
Introduction
Thromboembolic diseases are leading causes of cardiovascular-associated morbidity
and death [1-3]. Prevention and treatment of arterial thrombosis in patients with
cardiovascular diseases (e.g., atherosclerotic vascular disease, acute coronary syndrome
or ACS) are achieved using antiplatelet drugs [4], whereas venous thrombosis illnesses,
such as deep vein thrombosis (DVT) and pulmonary embolism (PE), are treated
with anticoagulant drugs that directly or indirectly inhibit various factors, mainly
thrombin (thr) and factor Xa (fXa), in the blood coagulation cascade [5,6].
Vitamin K antagonists (e.g., warfarin) and heparins have been the most prescribed
anticoagulants for > 50 years in a variety of conditions, including venous thromboembolism (VTE) and long-term prevention of ischemic stroke in patients with
atrial fibrillation (AF) [7]. Nonetheless, despite their proven efficacy, they share
several limitations. Warfarin carries the risk of serious bleeding, requires continuous monitoring for accurate dosing and its activity is affected by food and drug
interactions [8]. It has a narrow therapeutic window and unpredictable
pharmacokinetics, with marked inter- and intra-individual variability. Warfarin
10.1517/13543770903270532 © 2009 Informa UK Ltd ISSN 1354-3776
All rights reserved: reproduction in whole or in part not permitted
1
1535
Novel factor Xa inhibitors: a patent review
Intrinsic pathway
XIIa
Extrinsic pathway
VII
XIa
IXa
Warfarin
VIIa
Xa
Va
UFHs
LMWHs
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
YM-150
LY-517717
TAK-442
etc.
Dabigatran
Argatroban
Hirudins
Thrombin
V, VIII, XI activation (+)
Protein C activation (-)
Tissue
factor
Thrombin receptor activation
Fibrin generation
Figure 1. Scheme of the blood coagulation cascade with potential targets of selected anticoagulants. Several proteases in
both the extrinsic (tissue factor, factor VIIa) and intrinsic (factors XIIa, XIa, IXa) pathways converge upon activation of fXa in a common
pathway, in which thrombin plays a central role in either procoagulant (i.e., generation of fibrin from fibrinogen, stimulation of platelet
aggregation through activation of thrombin receptors, auto-amplification of its production through activation of factors V, VIII and XI) or
anticoagulant (i.e., thrombomodulin-assisted activation of protein C, which in turn slows down its conversion from prothrombin) actions.
Drugs are shown in boxes; the new oral anticoagulants (right boxes) include direct inhibitors of thrombin and fXa; the currently used
vitamin K antagonist warfarin and heparins are reported on the left side.
fXa: Factor Xa; LMWHs: Low molecular weight heparins; UFHs: Unfractionated heparins.
can also induce skin necrosis as a specific adverse reaction [9].
As for heparins, which are administered by injection,
complications include the need of laboratory monitoring for
dose adjustment and heparin-induced thrombocytopenia
(reduced with low molecular weight heparins, LMWHs) [10].
Because of these limitations, new anticoagulants, with stable
pharmacokinetics, better therapeutic windows and ease-of-use
than the existing ones, have been developed and are currently under advanced stages of clinical trials [7,11]. The combined use of antiplatelet and anticoagulant agents showed
additional benefits over anticoagulants alone in patients with
prosthetic heart valves [12] and in patients with AF [13,14].
Indeed, compounds combining anticoagulant and platelet
antiaggregatory activities in the same molecule are believed
to be promising drugs [15,16].
Among the novel anticoagulant drugs, orally administered
direct inhibitors of thr [17] and fXa [18] display better efficacy
and improved safety profile (e.g., bleeding). Ximelagatran
(exanta, AstraZeneca, Södertälje, SE), the first approved orally
1536
bioavailable direct thrombin inhibitor (DTI), was unfortunately
withdrawn from the market owing to its hepatotoxicity [19],
whereas in 2008 a second DTI, dabigatran etexilate (pradaxa,
Boheringer Ingelheim; Ingelheim am Rhein, DE) [20], which
proved to be as effective as the LMWH enoxaparin in
reducing the risk of VTE following joint-replacement
surgery [21], gained approval in the European Union and
Canada and is undergoing review by the US FDA [22].
Factor Xa, that is, a serine protease located at the confluence
of the intrinsic and extrinsic pathways of the blood coagulation
cascade, catalyzes the conversion of prothrombin to thrombin
via the prothrombinase complex (Figure 1). Due to its key
position in the blood coagulation cascade, fXa has emerged as
an attractive target for developing safer anticoagulant drugs.
Inhibition of fXa should prevent production of new thrombin
without affecting its basal level, which should ensure primary
hemostasis [23]. Hence, fXa inhibitors are predicted for having
lower risk of bleeding than heparins and warfarin [24], and
even higher therapeutic ratio than DTIs [25].
Expert Opin. Ther. Patents (2009) 19(11)
2
de Candia, Lopopolo & Altomare
Biochemistry &
molecular biology
6%
Hematology &
cardiovascular
diseases
39%
Pharmacology &
pharmacy
22%
B.
40
Number of publications
A.
fXa
thr
30
20
10
0
Drug design &
medicinal
chemistry
33%
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Years
Figure 2. Scientific publications on fXa inhibitors in the past 10 years, as retrieved by ISI web of knowledgeSM. A. Distribution
of publications (n = 648) in four major research fields. B. Number of publications dealing with small molecule fXa inhibitors (light gray
bars) in the field of drug design and medicinal chemistry (n = 208), compared to those pertaining to direct small molecule thrombin
inhibitors (n = 170, dark gray bars).
fXa: Factor Xa.
During the past 10 years, the number of publications
dealing with drug design and medicinal chemistry of small
molecule, selective and orally active fXa inhibitors has progressively increased, becoming higher than that of publications
pertaining to DTIs in the past 5 years (Figure 2). The growing
interest in these compounds is demonstrated by the active
participation of several pharmaceutical companies, and
documented by many patents published between 2006 and
April 2009, which are reviewed and discussed herein.
Structure-based drug design of small
molecule factor Xa inhibitors
2.
The design of selective small molecule fXa inhibitors has
profited from X-ray crystallography of several enzyme–inhibitor
complexes, molecular modeling and three-dimensional QSAR
studies [26]. Factor Xa contains a serine protease domain in a
trypsin-like closed β-barrel fold encompassing the catalytic
triad Ser195-His57-Asp102 and two essential subsites S1 and
S4. The search for ligands providing optimal interactions
within S1 and S4 pockets, combined with suitable scaffolds,
has been a major focus in structure-based design of selective
fXa inhibitors. Early fXa inhibitors contained benzamidine,
naphtylamidine or other basic groups [27], thought to be
necessary for binding in the S1 pocket, but the poor bioavailability often associated with the amidine group directed
efforts to replace this functionality with less basic or nonpolar
neutral groups [28,29]. Examples of benzamidine-containing fXa
inhibitors are DX-9065a (1), developed by Daiichi Pharmaceutical
Co. (Tokyo, JP) [30], and otamixaban (2), developed at
Sanofi-Aventis (Frankfurth aM, DE) [31]. DPC-423 (3),
disclosed by DuPont Pharmaceuticals (Newark, Delaware, US),
was the first orally active fXa inhibitor that went into
the clinic [32,33]. A range of potent and orally bioavailable
fXa inhibitors has since emerged, which include compounds containing either less basic amidine isosters, such as
razaxaban (DPC-906, 4) [34], or neutral P1 substituents,
such as rivaroxaban (BAY 59-7939, 5) [35] and apixaban
(BMS-562247-1, 6) [36].
X-Ray crystal structures of potent inhibitors in complex with
fXa (Figure 3) revealed that inhibitors bearing amidine or less
basic isoster (2 and 4) and neutral (5 and 6) P1 substituents
adopt L-shaped binding conformations.
The binding of otamixaban (2) and razaxaban (4) mainly
relies on the electrostatic interaction (reinforced by H-bonds)
of the basic P1 moiety with Asp189 at the bottom of the
S1 pocket, whereas the P4 moiety is embedded into the S4 site,
which is a box-shaped hydrophobic/aromatic cavity lined by
aromatic side chains of Tyr99, Phe174 and Trp215. Additional
H-bonds (sometimes mediated by water molecules), mainly
involving Gly219 or other residues at the proximity of the
S1 pocket entrance, stabilize the enzyme–ligand complexes.
The chlorothiophene substituent in rivaroxaban (5) is buried
inside the S1 pocket, with chlorine pointing towards the center
of the Tyr228 aromatic ring. The gain in binding energy due
to this hydrophobic contact, that is, the so-called chloro binding mode, could compensate the lack of electrostatic/H-bond
interactions between amidine and Asp189. Interestingly, even
in the presence of a benzamidine plus a chlorothiophene or
chlorobenzothiophene, the molecules interact by directing the
neutral group into the S1 pocket [37], thus demonstrating
that electrostatic interactions in S1 are not mandatory for
high affinity inhibitors. The chloro binding mode has been
reported for fXa inhibitors bearing other P1 substituents, such
Expert Opin. Ther. Patents (2009) 19(11)
3
1537
Novel factor Xa inhibitors: a patent review
-
O
HO
O
+
N
O
O
HN
N
H
N
O
O
P4
NH2
NH2
P1
NH
NH
2 Otamixaban (FXV-673)
1 DX-9065a
N
O
F
F
S
O
N
CF3
NH
CF3
NH
N
N
O
N
N
N
O
NH2
NH2
O
N
4 Razaxaban (DPC-906)
3 DPC-423
O
O
O
O
O
O
N
N
N
NH2
N
N
N
O
HN
O
P4
S
P1
O
Cl
5 Rivaroxaban (BAY 59-7939)
1538
6 Apixaban (BMS-562247-1)
Expert Opin. Ther. Patents (2009) 19(11)
4
de Candia, Lopopolo & Altomare
A.
B.
Gln192
S4
Glu97
Gln192
Tyr99
S4
Tyr99
Gly219
Phe174
Gly219
Phe174
Glu97
Trp215
Trp215
Ala190
S1
Ala190
S1
Asp189
C.
Asp189
D.
Gln192
S4
Glu97
Gln192
Tyr99
S4
Phe174
Gly219
Glu97
Trp215
Phe174
Gly219
Trp215
Ala190
Ala190
Tyr228
Tyr228
S1
Glu146
Tyr99
S1
Asp189
Asp189
Figure 3. X-ray crystal structures of otamixaban (A, pdb entry 1ksn), razaxaban (B, pdb entry 1z6e), rivaroxaban (C, pdb entry
2w26) and apixaban (D, pdb entry 2p16) in complex with human fXa. Only key amino acids of the essential S1 and S4 pockets are
displayed. H-bonds are shown as dashed lines; structural water molecules within 4 Å around the ligand are displayed with the symbol ×.
fXa: Factor Xa.
as, for example, chlorophenyl [38,39] and chloropyridine [40].
Apixaban (6), which instead bears 4-methoxyphenyl as
P1 substituent, adopts a similar binding mode, with the
para-methoxyphenyl group located in the S1 pocket [36].
3.
Therapeutic applications
Several oral fXa inhibitors are currently under various stages
of clinical development [11]. Among them, rivaroxaban 5
(Xarelto; Bayer Healthcare/Johnson & Johnson, Leverkusen,
DE), apixaban 6 (in co-development by Bristol-Myers Squibb,
Princeton, New Jersey, US, and Pfizer, Groton, US) and
edoxaban 9 (DU-176b, Daiichi Sankyo) [41] are in the most
advanced stages of development [42].
Rivaroxaban (5) has shown a favorable safety/efficacy balance
for preventing VTE after major orthopedic surgery [43]. It exhibited 60 – 80% oral bioavailability, achieving peak plasma level
in 3 h and half-lifes of 9 and 12 h in healthy young and
elderly subjects, respectively. Phase II clinical trials for VTE
prophylaxis following total knee replacement (TKR) [44] showed
that each single dose of rivaroxaban is well tolerated, with
predictable pharmacokinetics and pharmacodynamics at doses
≤ 40 mg, whereas adverse effects were somewhat elevated in
the 50 mg group [45,46]. Compared to enoxaparin in Phase III
studies examining VTE prevention following orthopedic
surgery, rivaroxaban revealed higher effectiveness [11].
Apixaban (6) is currently undergoing Phase III trials in VTE
prevention [11]. Displaying > 50% oral bioavailability and
half-life as between 9 and 14 h, it showed promising benefitrisk profile compared with the current standard of care in
patients following TKR [47]. The ADVANCE-1 study failed to
show non-inferiority to enoxaparin, whereas the results of the
ADVANCE-2 study, that is, a randomized, double-blind, multicenter trial comparing the efficacy of apixaban (2.5 mg orally
b.i.d.) with enoxaparin (40 mg/day s.c.) for thromboprophylaxis after TKR, have been presented in July 2009 [48]. Taken
together, the results of the ADVANCE studies indicate a
favorable risk-benefit profile of apixaban relative to approved
enoxaparin regimens. Moreover, it entered Phase III trials
for stroke prevention and Phase II studies for ACS [42].
Edoxaban (DU-176b, 9), a potent and highly selective fXa
inhibitor built up on cis-2-aminocyclohexylamine scaffold,
significantly reduced both venous and arterial ex vivo thrombus
formation, ≤ 5 h post-dose [49-51]. The Phase II program has
been successfully completed for orthopedic and cardiological
indications, and a dose-ranging study provided crucial insight
with regard to optimal dosage of edoxaban for a Phase III study
(ENGAGE-AF TIMI 48) aimed at seeking approval for AF [52].
Expert Opin. Ther. Patents (2009) 19(11)
5
1539
Novel factor Xa inhibitors: a patent review
Other fXa inhibitors in earlier stages of clinical development include YM-150 (Astellas Pharma, Inc., Tokyo, JP;
formerly Yamanouchi), LY-517717 (8, Eli Lilly & Co.,
Indianapolis, Indiana, US), betrixaban (PRT-054021, 10; in
co-development by Merk, Darmstadt, DE, and Portola
Pharm., Inc., San Francisco, California, US) and TAK-442
(Takeda Pharm. Co., Osaka, JP) [7,11,53].
YM-150, whose structure is not known, is most likely a
compound representing the second generation class of
compounds that replaced YM-60828 (7) [54,55]. The compound
has a Ki for fXa of 31 nM. In a randomized, open-label, doseescalation Phase IIa study for the prevention of VTE in patients
undergoing THR (H is for ‘hip’), a significant dose–response
relationship was observed and no major bleeding events were
reported. Oral administration at doses of 10 – 60 mg was
shown to be well tolerated and effective. Further investigation
will continue in the continuing large-scale Phase IIb study
(ONYX-2). YM-150 also entered into Phase II dose-finding
trials for stroke prevention in patients with AF.
LY-517717 (8), an indole caboxamide derivative of D-phenylGly, which selectively inhibits fXa with a Ki of 4.6 – 6.6 nM,
achieves plasma peak concentration within 0.5 – 4 h after
oral administration and elimination half-life of about 27 h
in healthy volunteers. In a randomized, double-blind, doseescalation Phase II study in patients undergoing TKR and
THR, it exhibited dose-dependent efficacy with a similar
incidence of bleeding to enoxaparin for the VTE prevention.
Betrixaban (10) inhibits fXa with a Ki of 0.1 nM. It has
an oral bioavailability of 47% and half-life of 19 h (excreted
almost unchanged in bile). The completed Phase II clinical
trials in patients undergoing TKR surgery provided proofs
for efficacy and safety of betrixaban (15 or 45 mg b.i.d.)
compared with enoxaparin (30 mg b.i.d.) in > 200 patients.
Further Phase II studies have also been planned for investigating betrixaban in VTE prevention and treatment, stroke
prevention in AF and secondary prevention of stroke and
myocardial infarction.
The Takeda’s novel fXa inhibitor TAK-442 (structure not
reported) for venous and arterial TE treatment has entered into
Phase II clinical stage in the US and in Europe. Recently reported
preclinical findings [56] suggest that TAK-442 may be more
effective than fondaparinux in preventing arterial thrombosis
in patients undergoing percutaneous coronary interventions.
4.
Survey of the patent literature
An overview of the patents filed during the period 2000 – 2005
has been reported [29]. Herein, we review advances published
in the patent literature between 2006 and April 2009.
During this period, > 100 patents on novel fXa inhibitors,
claimed by ∼ 30 companies, have been published. Bayer
HealthCare contributed for 20% out of the total number of
the filed patents, followed by Boehringer Ingelheim (11%),
Hoffmann-La Roche (Basel, CH) (10%), Bristol-Myers Squibb
(8%), Millennium Pharmaceuticals (Cambridge, Massachussets,
1540
US) (6%) and others. The key players in the area were Bayer,
Bristol-Myers Squibb, Daiichi and Eli Lilly. Almost all other
contributors highlighted new structure–activity relationships
pertinent to scaffolds and/or P1 and P4 moieties.
A few patents deal with compounds bearing benzamidine
or its mimics as P1 groups, whereas the majority describes fXa
inhibitors containing neutral lipophilic groups as S1 binding
moieties. Data on inhibitory activity (e.g., IC50, Ki, Kass),
selectivity and other biological properties will be presented as
reported in the original publications.
Amidine-based factor Xa inhibitors and less basic
analogues
4.1
Bis-amidine derivatives, built up using 2-phenoxyethyl benzoate
as scaffold, were disclosed by Ajinomoto Co. (Tokyo, JP) and
claimed as inhibitors of fXa with good in vitro anticoagulant
properties [57]. The most potent inhibitor 11 (IC50 = 3 nM)
proved to be selective versus thr. Alkylation, and not acylation,
of the phenol OH, as well as the replacement of the S4
binding moiety imino(pyrrolidinyl)methyl with the iminoethylpiperidinyloxy group (12, Ki = 63 nM), resulted in a
significant decrease of the inhibitory activity.
Curacyte Chemistry GmbH (Jena, DE) has patented a
series of highly potent and selective fXa inhibitors, designed
as substrate analogues. They include either 4-amidino- (13, 14)
or 2-(aminomethyl)-5-chloro-benzylamide (15 – 17 )
derivatives [58-60]. Compound 13, containing a residue of
D-homophenylalanine (D-hPhe), exhibited high inhibition
potency (Ki = 0.6 nM), but low selectivity versus thr and
very short plasma half-life (< 20 min). In an effort to improve
potency, selectivity and pharmacokinetic profile, D-hPhe was
replaced by other aromatic homo amino acids, and better
inhibition potency and selectivity were achieved by introducing D-homo-2-pyridylalanine or its pyridine N-oxide analogue [58]. Compound 14 was designed taking into account
that incorporation of the π-deficient pyridine N-oxide may
reinforce aromatic interactions with the aryl binding site
(S3/S4 pocket). Substitution of the N-terminal benzylsulfonyl group with alkylsulfonyl groups led to less potent
inhibitors. Compound 14 exhibited excellent in vitro anticoagulant potency and high selectivity, but proved to have
poor oral bioavailability and to be rapidly eliminated after
intravenous administration. To overcome these problems,
4-amidinobenzylamide was replaced with less basic residues,
such as 2-(aminomethyl)-5-chloro-benzamide. Compounds 15 –
17 retained high fXa affinity, but moderate selectivity
against thrombin, and compound 15 emerged as a more potent
inhibitor than the corresponding benzamidine derivative 14,
showing good anticoagulant activity, as assessed in clotting
assays as the concentration that doubles activated partial tromboplastin time (2 × aPTT = 0.16 μM). The replacement of
the Gly with Pro led to increase of fXa selectivity, whereas
D-hTyr in compound 17 did increase affinity for thrombin.
Morphochem Chemie Co. (München, DE) has registered
a number of 3-benzamidino derivatives of phenylglycine
Expert Opin. Ther. Patents (2009) 19(11)
6
de Candia, Lopopolo & Altomare
O
O
O
OH
S
NH
N
H2N
N
NH
O
7 YM-60828
O
S
N
NH
O
N
H
N
N
H
O
N
O
O
H
N
NH
N
O
N
N
N
Cl
8 LY-517717
9 Edoxaban (DU-176b)
HN
O
N
HN
O
O
NH
N
Cl
10 Betrixaban (PRT-054021)
(PhGly) [61,62]. In these compounds, the α-NH2 group of
the PhGly scaffold is connected to 3-amidinophenyl group
(18 and 20) or 5-amidino-2-hydroxyphenyl group (19) as P1
moieties, and the α-COOH to 4-methyl-piperazinyl (18),
4-methyl-1,4-diazepan-1-yl (19) and 1-(2-methoxyphenyl)
piperazinyl (20) groups as P4 moieties.
An unusual feature of these inhibitors is represented by
β-D-glucose linked at the ortho position of the PhGly. Derivatives belonging to both S and R series inhibited fXa at nanomolar
concentrations and showed good ex vivo anticoagulant
properties (S-enantiomers were slightly more active than
R-enantiomers). In general, a suitable dose ranging from 0.1 μg
to 10 mg/kg/day has been established. As tumor cells express
several procoagulant activities, which may be involved in
hemostasis disturbances and metastasis mediated by the action
of serine proteases on the proteinase activated receptor, some of
these derivatives have been assayed for their ability to interfere
with cellular proliferation in different cancer cell lines. Interestingly, compound 20 (MCM-09) was found to inhibit melanoma
lung cancer colonies in mice in a dose-dependent manner [63].
Janssen Pharmaceutical Co. (Beerse, BE) disclosed a
high-affinity 7-fluoroindazole-based fXa inhibitor (21, fXa
Ki = 1 nM) [64]. Application of 1,2-benzisoxazol-3-amine as
a bioisosteric replacement for the benzamidine moiety and
Expert Opin. Ther. Patents (2009) 19(11)
7
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Novel factor Xa inhibitors: a patent review
O
OH
O
O
N
NH
H 2N
NH
11
NH
O
O
O
O
N
O
H2N
NH
12
+
N
-
O
O
O
O
H
N
S
O
H
N
S
N
H
N
H
O
O
O
NH
O
NH
NH2
NH2
NH
NH
13
14
diverse P4 groups gave compounds (22 – 24) that exhibited fXa
Ki values in the low nanomolar range.
The 7-fluoroindazole scaffold seems to reduce the in vivo
metabolic susceptibility [65]. Moreover, 7-F substituent, as well
as the addition of a second fluorine on the 6-phenyl group,
enhanced potency. A significant increase in potency was
achieved by introducing 3-CONH2 group (and not 3-CH3 or
3-CF3), as exemplified by compound 22 (fXa Ki = 6.5 nM),
which displayed good selectivity against thr and trypsin, but a
low in vitro anticoagulant activity (2 × aPTT > 90 μM). The
investigation on basic P4 moieties led to the pyridine-containing
derivative 23 (fXa Ki = 4 nM), and optimization studies led
to the identification of compound 24, endowed with good
1542
in vitro anticoagulant properties and Caco-2 cell permeability.
7-Fluoroindazole derivatives bearing benzylamine as
P1 element (25, 26) were also reported, which showed lower
fXa inhibition potency and poorer selectivity versus trypsin.
In two very recent patents, mainly dealing with oxazolidinonebased fXa inhibitors [66,67], Schebo Biotech AG (Giessen, DE)
has also described a number of amidine-based compounds
(e.g., 27 – 31), including potential prodrugs (29, 30) and glicosyl
derivatives (31), but no biological data have been provided.
Bristol Myers Squibb disclosed razaxaban (DPC-906, 4)
in 2005 [34]. Then, a series of 3-trifluoromethyl pyrazole5-carboxamide derivatives were patented [68,69], in which
1,1′-biphenyl-2-sulfonamide (32 – 36) group is fixed as
Expert Opin. Ther. Patents (2009) 19(11)
8
de Candia, Lopopolo & Altomare
+
+
-
N
N
O
-
O
O
O
O
HO
N
H
N
S
N
H
N
H
NH
O
O
O
O
Cl
NH
Cl
NH2
NH2
15
16
OH
HO
N
N
H
O
O
O
NH
Cl
NH2
17
P4 element and different arginine-mimetic fused heterocycles,
such as quinazolin-4-amine (32), phtalazin-1-amine (33),
1H-isoindol-4-amine (34) and 1,2-benzisoxazol-3-amine (35, 36),
investigated as P1 moieties. The most promising compounds
were claimed for exhibiting fXa Ki values ≤ 1 nM.
Factor Xa inhibitors bearing neutral P1 binding
moieties
4.2
Privileged neutral substituents, which interact with the
S1 pocket through the ‘chloro binding mode’ and improve
oral bioavailability, are 2-chlorothiophene, 3-chloropyridine,
chlorobenzene, methoxybenzene, 2-chloronaphtalene and
5-chloro-1H-indole. While the molecular scaffolds may largely
vary, there are a number of recurrent P4 substituents, among
which pyridine-2(1H)-one, piperidin-2-one, morpholin-2-one,
benzenesulfonamide, variously fused piperidines and
benzazepines are the most privileged ones.
In the past 3 years, Bayer HealthCare company has registered the greatest number of patents in the area. Most of
their disclosures deal with new rivaroxaban-like compounds,
their administration forms and use in prevention and treatment of thromboembolic disorders. A series of 2-iminooxazolidine derivatives, structurally related to rivaroxaban 5 (fXa
Ki = 0.4 nM), has been reported. Compound 37, exhibiting
IC50 = 5.4 nM and ∼ 2,000-fold selectivity versus thr, is a
representative example [70].
Expert Opin. Ther. Patents (2009) 19(11)
9
1543
Novel factor Xa inhibitors: a patent review
OH
OH
OH
HO
OH
HO
O
OH
O
OH
O
N
O
O
N
O
N
N
H
N
N
H
HN
O
NH
HN
O
NH2
HO
HN
NH2
19
18
OH
OH
HO
O
O
OH
O
N
O
N
N
H
O
HN
HN
NH2
20 MCM-09
In other series, the morpholinone P4 moiety was
replaced with 2-iminooxazolidine [71], morpholine [72,73]
and 2-aminoethoxyacetic acid [74]. Compounds 38 (fXa
IC50 = 1.1 nM), 39 (IC50 = 43 nM) and 40 (IC50 = 32 nM)
shed light on structure–activity relationships of P4 elements.
Replacing Cl in chlorothiophene with Br led to a twofold
increase of fXa inhibition potency (41, IC50 = 0.3 nM; rivaroxaban, IC50 = 0.7 nM) [75]. In vivo data from the AV shunt
model in rat were reported along with results from thrombin
generation assay in human platelet rich plasma (PRP), in which
compound 41 has been tested alone and in combination with
aspirin or clopidogrel. One patent [76] covered a number of
compounds bearing fluorine at the ortho position of the
phenyl ring, two representative potent fXa inhibitors
1544
being compounds 42 and 43. Irrespective of their diverse
P4 elements, they displayed the same inhibition potency
(fXa IC50 = 0.9 nM). Bayer laboratories have reported other
series of oxazolidinone-based compounds, which vary either
for substituents on the phenyl ring or P4 moieties. Compounds 44 – 47 exemplify these series, but the enzyme data
showed that none of them achieved inhibition potency and
selectivity close to rivaroxaban. Indeed, compounds 44 and
45 [77] were both reported with IC50 values of 11 nM for fXa,
but 10 and 34 nM, respectively, for thr. Compound 46 [78]
inhibited fXa and thr with IC50 values of 21 and 198 nM,
respectively, whereas, as shown by compound 47 [79], the
introduction of the cyclopropyl group at the meta position
of the P3 phenyl group and ring expansion of the P4 moiety
Expert Opin. Ther. Patents (2009) 19(11)
10
de Candia, Lopopolo & Altomare
O
O
N
F
O
NH2
N
N
N
N
F
N
F
NH2
NH2
O
HN
21
N
22
N
N
O
O
N
NH2
N
NH2
N
N
F
N
F
N
N
NH2
NH2
O
O
N
23
N
24
O
N
N
N
N
F
N
Cl
N
F
N
N
H2N
H2N
25
26
Expert Opin. Ther. Patents (2009) 19(11)
11
1545
Novel factor Xa inhibitors: a patent review
HO
-
O
O
+
N
HN
O
O
N
H
N
O
NH
O
O
O
NH2
NH2
HN
HN
27
28
O
O
O
O
N
N
NH
N
O
N
N
NH
O
O
O
HN
O
H2N
NH2
O
N
O
OH
N
29
30
OH
OH
O
O
O
H
N
OH
N
N
NH
O
O
HN
31
1546
OH
Expert Opin. Ther. Patents (2009) 19(11)
12
NH2
de Candia, Lopopolo & Altomare
SO2NH2
SO2NH2
CF3
NH
N
N
O
CF3
NH
N
N
O
NH2
NH2
N
N
N
N
32
33
SO2NH2
SO2NH2
CF3
NH
O
N
CF3
NH
N
N
O
NH2
NH2
O
N
N
N
34
35
N
N
CF3
NH
N
O
N
NH2
O
N
36
Expert Opin. Ther. Patents (2009) 19(11)
13
1547
Novel factor Xa inhibitors: a patent review
O
HN
N
N
O
O
O
O
N
N
O
HN
O
HN
O
S
S
Cl
Cl
37
38
O
O
HOOC
O
O
O
O
N
N
O
HN
N
HN
HN
O
S
S
Cl
Cl
39
40
O
O
O
O
O
O
O
N
N
O
N
N
F
HN
HN
O
S
S
Cl
Br
41
1548
O
42
Expert Opin. Ther. Patents (2009) 19(11)
14
O
de Candia, Lopopolo & Altomare
resulted in a marked decrease of fXa/thr selectivity (fXa
IC50 = 25 nM; thr IC50 = 34 nM).
As for oxazolidinone derivatives, Bayer has also registered a
few patents pertaining to methods for treating thromboembolic
disorders (e.g., dosage) [80], controlled-release oral administration form [81], formulation for prophylaxis and treatment of
pulmonary hypertension [82] and therapeutic use in prevention
and treatment of disseminated intravascular coagulation, septic
shocks, septic organ dysfunction and failure [83].
Other disclosed potent fXa inhibitors are exemplified by
the 4,5-dihydroisoxazole derivative 48 (IC50 = 7.9 nM) and
pyrazole derivative 49 (IC50 = 1.4 nM) [84].
Bayer has reported further potential anticoagulants that
incorporate isoindolin-1-one as central core. Two isomer
compounds, namely 50 and 51, exhibited fXa IC50 values of
1.2 and 5.3 nM, respectively [85]. Compound 52 was found
to inhibit fXa with an IC50 of 1.1 nM [86,87]. Compounds
53 – 56 are four further potent fXa inhibitors, representative
of series reported in as many recent patents, which exhibited
subnanomolar IC50 values. The pyrazole-related derivative 53
displayed IC50 of 0.8 nM [88], and even more potent inhibitors resulted in the pyrazine dicarboxamide derivative 54
(IC50 = 0.16 nM) [89], the 2-methylthiazol dicarboxamide
derivative 55 (IC50 = 0.30 nM) [90] and the anthranilamide-based
compound 56 (IC50 = 0.66 nM) [91].
Boehringer Ingelheim has reported several derivatives bearing
2-chlorotiophene as P1 element. As exemplified by structure 57,
some of them incorporate 1-aminocyclopropanecarboxylic acid
as the central template [92] and 3-methyl-2,3,4,5-tetrahydro1H-3-benzazepine as S4 binding motif. Other patents disclosed
compounds with pyrrolidin-2-one and other five-membered
rings, including imidazole and oxadiazole, as central templates,
and either basic or neutral P4 moieties, as illustrated by
structures 58 – 62 [93-96].
A variety of fXa inhibitors, containing 3-chloropyridine (63,
64), chlorobenzene (65) and 5-chloro-1H-benzimidazole (66,
67) as the P1 moieties, and 2-methyl-1,2,3,4-tetrahydroisquinoline, 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and
morpholin-2-one as suitable P4 substituents, has been
reported [97-101]. In addition, one patent deals with fXa
inhibitors bearing 2-ethynylthiophene as P1 element (68) [102],
whereas a more recent patent described azetidine dicarboxamide derivatives bearing bromobenzene as P1 moiety
(e.g., 69) [103]. All these compounds were claimed for inhibiting
fXa with IC50 values < 100 μM.
Recent papers reported 1,2-cis-(1R,2S)-cyclopentyldiamine
and cyclohexylamine derivatives [104,105]. A series of nonbasic
selective fXa inhibitors, built up using a central cycloalkyl
dicarboxylic acid scaffold [106,107], has been patented from
Hoffman-La Roche. In an attempt to improve activity and oral
bioavailability, the dicarboxylic acid moiety was replaced by
different aliphatic cyclic amino acids, affording compounds
70 – 72 [108], which bear 5-chlorothiophen-2-carboxamide as
P1 moiety. The most potent fXa inhibitor 70 exhibited fXa
Ki value of 6 nM. An important feature was shown to be
the alkoxy side chain at C-4 of the cyclopentane ring, the
ethoxy group providing the most favorable effect. The hydroxy
congener of 70 and compound 71 had been found to be
3 times less potent than 70. Moreover, alkyl groups longer and
more sterically hindered than the ethyl group did not enhance
the activity, as well as the replacement of the ethoxy side chain
with 2-oxopropyl group (72, Ki = 30 nM) [108].
A focused screen on the Roche compound collection
allowed the 2-aminothiazole-based fXa inhibitor 73 to be
identified (Ki = 112 nM) [109,110]. Unfortunately, it failed to
display optimal anticoagulant activity in vitro (2 × aPTT =
70.1 μM), most likely because of its high lipophilicity. Hence,
N-substituted piperazines were investigated as P4 elements,
and compounds 74 (Ki = 442 nM, 2 × aPTT = 32 μM) and 75
(Ki = 32 nM, 2 × aPTT = 4.4 μM) resulted by far superior
with respect to fXa inhibition potency and in vitro/ex vivo
clotting assays [109]. The thiazole core was also replaced by
various 5-membered nitrogen heterocycles, such as pyrazole,
1,3,4-triazole (76) and tetrazole. Compound 76 displayed
excellent in vitro activity (fXa K i = 6 nM, 2 × aPTT =
2 μM) [109]. Finally, 3-aminopyrrolidine derivatives (77 – 79),
in R-configuration, exhibited excellent Ki values [111], and
compound 77 emerged as the most potent compound in this
series (fXa Ki = 3 nM). Removal of the methoxy group or
introduction of larger substituents led to a loss of activity [111].
Unfortunately, compound 77 is rapidly metabolized by human
and rat microsomes, whereas the corresponding hydroxyl
derivative showed better microsomal stability. A good fXa
inhibitory potency was achieved by the trifluoromethyl
derivative 78 (Ki = 8 nM), in which curiously chlorothiophene
was replaced by the t-butoxycarbonyl group [111]. A recent
disclosure is represented by compound 79 (Ki = 23 nM).
Other patents deal with compounds containing various
cycloalkyl dicarboxylic acids as central scaffolds [106,107].
Among them, compound 1S,2R-80 exhibited Ki value of 3 nM,
and improvements were claimed for a number of derivatives
(e.g., 81 – 84) [106,107].
Promising results were obtained with the spirocyclic
derivative 5S,6S-82 (Ki = 8 nM), rac-83 (Ki = 9 nM) and
1S,2S,4S-84 (Ki = 8 nM). In vitro anticoagulant assays showed
good efficacy (2 × aPTT values in the 0.5 – 10 μM range).
The patented synthesis of cyclopentan-1,2-dicaboxamides is
illustrated in Figure 4. Oxidation of the exocyclic methylene
group by periodate cleavage or epoxidation afforded the
cyclopentanones or the corresponding spyrocyclic epoxides
as useful starting materials for subsequent reactions.
In 2007, Hoffman-La Roche filed two patents on
compounds bearing 4-chlorophenyl and pyridine-2(1H)-one
as P1 and P4 moieties, respectively, exemplified by compounds
85 – 90 [112,113], which contain fused azaheterocyclic nuclei
as central cores. These compounds exhibited good in vitro
anticoagulant properties, as assessed by concentrations doubling
prothrombin time (PT) and aPTT, ranging from 0.5 to 10 μM,
and nanomolar fXa Ki values. Pyridine fused cyclic amine
derivatives 86 (Ki = 51 nM) and 87 (Ki = 12 nM) resulted
Expert Opin. Ther. Patents (2009) 19(11)
15
1549
Novel factor Xa inhibitors: a patent review
HO
NH
HO
O
O
O
O
O
O
N
N
N
N
F
HN
O
HN
O
S
O
S
Cl
Cl
43
44
HO
HN
O
O
O
O
N
N
HN
O
S
Cl
45
HO
O
O
O
O
O
O
N
N
N
N
O
HN
HN
O
S
S
Cl
Cl
46
1550
47
Expert Opin. Ther. Patents (2009) 19(11)
16
O
de Candia, Lopopolo & Altomare
N
N
O
N
N
N
O
O
NH
NH
HN
HN
O
S
S
Cl
Cl
48
O
49
N
O
O
O
O
N
O
N
O
HN
N
HN
O
O
S
S
Cl
Cl
50
51
O
N
O
N
N
NH
NH2
N
O
N
O
O
HN
N
O
O
S
O
Cl
52
53
Expert Opin. Ther. Patents (2009) 19(11)
17
1551
Novel factor Xa inhibitors: a patent review
O
N
N
N
NH
NH
N
O
O
O
N
S
O
NH
O
O
NH
NH
N
N
Cl
Cl
54
55
N
H
N
O
HN
O
N
O
S
NH
Cl
56
in less potent compounds than corresponding benzene fused
analogues 89 (3,4-dihydro-1 H -isoquinoline series) and
90 (2,3-dihydroisoindole series), both displaying Ki of 2 nM.
In several patents, Bristol-Myers Squibb disclosed a family
of anthranilamide-based fXa inhibitors, bearing chloropyridine
and pyridine-2(1H)-one as P1 and P4 binding moieties,
respectively [114,115]. Specific biological data were not reported,
whereas a recent publication provided information on compounds 91 and 92, which exhibited fXa Ki values in the
picomolar range (≤ 0.06 nM), good oral bioavailability, lowto-moderate clearance and half-life shorter than apixaban [116].
In another application, Bristol-Myers Squibb claimed
cyclic β-amino acids based derivatives, such as compounds
93 – 95 [117]. The most potent inhibitors showed fXa
inhibition constants < 1 nM.
As reported earlier, in 2005 Bristol-Myers Squibb disclosed
razaxaban (4, DPC-906) and investigated a series of its analogues. These studies revealed that compounds belonging to
pyrazole carboxamide series may undergo in vivo hydrolysis
with liberation of potentially mutagen biarylaniline
compounds [34]. Then, a great deal of efforts was made to find
more in vivo stable fXa inhibitors, pursuing several strategies,
1552
which mainly consist in incorporating the amide group into
a bicyclic lactam structure and replacing anilines with cycloalkylamines. A lot of new compounds, including carboxamide
and dione derivatives of pyrazolo[3,4-c]pyridine (96, 97),
pyrazolo[4,3-d]pyrimidinone (98), pyrazolo[3,4-d]pyridazinone (99) and pyrazolo[3,4-c]azepinone (100), were synthesized
and patented [118-123].
Compounds bearing 4-methoxyphenyl and biphenyl2′-sulfonamido as P1 and P4 residues, respectively, proved
to be potent fXa inhibitors, with Ki values in the range of
1 – 40 nM. Unfortunately, aPTT clotting assay revealed poor
anticoagulant properties in compounds containing pyrazolo
[3,4-d]pyridazinone, pyrazolo[3,4-c]azepinone and pyrazolo
[4,3-d]pyrimidin-5,7(4H, 6H)-dione as bicyclic core, because
of their high binding to plasma proteins. Promising results were
instead obtained with derivatives of pyrazolo[3,4-c]pyridinone
and pyrazolo[4,3-d]pyrimidinone, the most active compounds showing 2 × aPTT values in the low micromolar
range [118,119]. In the development of bicyclic lactam derivatives
belonging to the pyrazolo[3,4-c]pyridine-7-one family
(general structure 101), diverse P4 moieties and substituents
at C-3 of pyrazole ring have been introduced (general
Expert Opin. Ther. Patents (2009) 19(11)
18
de Candia, Lopopolo & Altomare
O
H
N
NH
N
NH
N
O
O
N
O
S
S
Cl
Cl
57
58
O
N
O
O
O
F
N
N
O
N
N
O
HN
NH
O
S
S
Cl
Cl
59
60
O
S
O
O
O
N
O
HN
O
N
O
N
N
N
N
HN
HN
O
O
S
S
Cl
Cl
61
62
Expert Opin. Ther. Patents (2009) 19(11)
19
1553
Novel factor Xa inhibitors: a patent review
HO
O
Cl
O
H
N
N
O
N
N
H
N
O
NH
NH
O
N
N
Cl
Cl
64
63
O
O
O
H
N
O
O
N
N
HN
N
O
F 3C
NH
NH
O
N
Cl
Cl
65
66
O
O
N
NH
O
O
N
H
N
NH
O
H
N
O
N
S
Cl
67
68
O
H
N
N
NH
N
O
O
Br
69
1554
Expert Opin. Ther. Patents (2009) 19(11)
20
de Candia, Lopopolo & Altomare
F
O
N
O
NH
O
O
N
H
S
Cl
70
O
N
F
N
OH
NH
O
O
N
H
S
Cl
71
O
N
O
F
N
NH
O
O
N
H
S
Cl
72
O
N
F
NH
O
N
NH
S
O
Cl
73
Expert Opin. Ther. Patents (2009) 19(11)
21
1555
Novel factor Xa inhibitors: a patent review
N
N
O
N
S
O
N
N
H
S
Cl
74
O
N
O
N
N
S
N
NH
O
Cl
75
O
F
NH
N
O
N
O
N
N
H
N
S
Cl
76
O
N
F
NH
O
O
N
N
H
O
S
Cl
77
1556
Expert Opin. Ther. Patents (2009) 19(11)
22
de Candia, Lopopolo & Altomare
F
O
NH
N
O
N
NH
F 3C
O
O
78
O
N
F
H
N
NH
. CF COOH
3
O
O
N
H
S
Cl
79
structures 102 – 104) [120]. Compounds 105 (Ki = 0.3 nM) and
106 (Ki = 0.03 nM, 2 × PT = 1.2 μM) exhibited promising
anticoagulant activity and good pharmacokinetic profile in
dogs [120-124]. In order to reduce the potential risk of releasing
in vivo mutagenic biarylanilines, the 6-phenyl group was
replaced with a piperidine one, leading to derivatives such as
compound 107 [125]. The introduction of pyridin-2(1H)-one
led to apixaban (6, BMS-562247-1, Ki = 0.08 nM, 2 × PT =
3.8 μM) [36], which proved to be effective in inhibiting both
free and clot-bound fXa and is currently undergoing advanced
stages of clinical trials [126-128].
Most of the patents registered by Millennium Pharmaceuticals reported fXa inhibitors incorporating various
5-membered heterocycle rings as central cores and
5-chlorothiophene-2-carboxamide as constant P1 moiety.
Compound 108 [129] exhibited fXa IC50 at concentration
< 100 nM. A series of imidazole derivatives, exemplified
by compounds 109 and 110 [130], both bearing pyridine2(1H)-one as P4 group, proved to be in vitro inhibitors of
fXa (IC50 ≤ 100 nM), but the impact of 2-oxopiperazine at
the ortho position of the P3 phenyl group cannot be assessed
(no specific biological data provided). For compound 111,
pharmacokinetic data in rat, dog and monkey after oral or
intravenous administration were given. 1,2,3-Triazole
derivatives, exemplified by compounds 111 and 112 [131,132],
have been also reported and the respective in vitro fXa IC50
values claimed to be ≤ 100 nM. Methods for preparing
suitable pharmaceutical salts and polymorphs of the
anthranilamide derivative betrixaban (10) have been
described [133,134]. As reported in recent publications [135,136],
compounds belonging to this series are highly potent
and orally bioavailable fXa inhibitors. In thrombin
generation assay in human platelet rich plasma (PRP),
combination of compound 10 (15.6 nM) with aspirin proved
to be successful (26.9% inhibition versus 5.1% inhibition
without aspirin) [137].
The pyrrolidinone series of fXa inhibitors disclosed by
GlaxoSmithKline (Greenford Middlesex, GB) was already
discussed in previous patent review [29]. Further reported
compounds incorporate various benzofused cyclic amines as
S4 binding moiety. Compound 113, representative of this
series [138], has been claimed as active principle in modified
pharmaceutical composition for oral administration [139,140].
Some Glaxo patents reported introduction of diverse polar
groups on the sulfonamide nitrogen or in P4-position [141,142].
Specific biologic data were not reported, but in medicinal
chemistry literature compound 114 (fXa Ki = 4 nM), which
exhibited appreciable selectivity versus thr (Ki = 367 nM)
and oral bioavailability (%F = 75% in Sprague-Dawley rats),
as well as reduced binding to human serum albumin and good
anticoagulant effects (1.5 × PT = 1.2 μM), was identified as
one of the most attractive candidates for further developments [143]. Interestingly, small modifications at the double
bond led to different selectivity ratios [144]. Thus, the saturated
Expert Opin. Ther. Patents (2009) 19(11)
23
1557
Novel factor Xa inhibitors: a patent review
Mono
saponification
R1NH2
Coupling
O
HO
O
Saponification
R2NH2
R1
H
N
OH
O
O
O
R2
Epoxidation
O
NH
NH
R1
R2
O
Periodate
cleavage
R3
O
H
N
NH
R1
O
O
O
+
Coupling
HN
O
R1
O
O
O
O
HN
O
O
R3NH2
reductive
amination
H
N
H
N
R1
O
O
R2
R1
H
N
NH
NH
O
R2
O
R1
NH
O
R4OH
ring-opening
Reduction
OH
R1
H
N
NH
O
OR4
HO
H
N
R2
O
R2
O
R1
NH
O
O
R2
Figure 4. Synthetic pathway for a series of cyclopentan-1,2-dicarboxamide derivatives patented by Hoffman-La Roche as
fXa inhibitors.
fXa: Factor Xa.
1558
Expert Opin. Ther. Patents (2009) 19(11)
24
de Candia, Lopopolo & Altomare
O
O
N
F
O
NH
N
F
O
N
NH
O
HN
O
F
HN
O
F
N
Cl
Cl
80
O
81
F
O
F
HO
N
N
NH
NH
O
O
O
O
O
NH
NH
Cl
Cl
82
O
83
F
O
F
N
N
OH
NH
N
N
NH
O
O
O
N
HN
NH
O
Cl
Cl
84
85
Expert Opin. Ther. Patents (2009) 19(11)
25
1559
Novel factor Xa inhibitors: a patent review
O
F
O
N
F
N
NH
NH
N
N
O
N
O
N
O
HN
O
NH
Cl
Cl
86
O
87
O
F
N
F
N
NH
NH
N
O
O
O
HN
O
NH
Cl
Cl
88
89
O
F
Cl
O
N
N
NH
HN
S
Cl
90
1560
N
Expert Opin. Ther. Patents (2009) 19(11)
26
O
de Candia, Lopopolo & Altomare
O
O
O
F
O
O
N
O
N
HN
Cl
HN
O
O
NH
NH
N
N
Cl
Cl
91
O
F
92
O
O
N
Cl
F
O
N
NH
N
NH
HN
HN
O
O
N
N
Cl
Cl
93
94
O
O
S
O
F
N
O
NH
N
HN
O
N
Cl
95
Expert Opin. Ther. Patents (2009) 19(11)
27
1561
Novel factor Xa inhibitors: a patent review
SO2NH2
SO2CH3
CF3
N
N
CF3
N
N
N
N
O
N
O
O
O
97
96
SO2NH2
SO2NH2
N
N
CF3
CF3
N
N
N
N
N
O
N
O
O
O
99
98
SO2NH2
N
n
N
N
O
O
R3
CF3
N
O
N
N
O
O
101
100
1562
N
Expert Opin. Ther. Patents (2009) 19(11)
28
de Candia, Lopopolo & Altomare
N
R
N
R
CF3
CF3
N
N
N
N
N
O
N
O
O
O
102
103
N
N
O
N
R3
N
N
NH2
N
N
N
O
N
O
O
O
104
105
HO
N
N
O
O
N
NH2
N
NH2
N
N
N
N
O
N
O
O
O
106
107
Expert Opin. Ther. Patents (2009) 19(11)
29
1563
Novel factor Xa inhibitors: a patent review
O
N
N
O
N
N
NC
HN
HN
O
O
S
S
Cl
Cl
108
109
NH
O
O
N
O
HN
N
N
N
N
HN
N
N
N
HN
O
S
S
Cl
Cl
110
111
NH
O
N
N
N
N
N
HN
S
Cl
112
1564
Expert Opin. Ther. Patents (2009) 19(11)
30
O
O
de Candia, Lopopolo & Altomare
O
NH
N
NH
N
N
SO2
O
SO2
O
O
HN
S
S
Cl
Cl
113
114
O
F
NH
N
N
NH
N
SO2
SO2
O
O
O
HN
S
Cl
Cl
115
116
derivative reverted the selectivity ratio (fXa Ki = 154 nM,
thr Ki = 17 nM) and the propenyl derivative 115 resulted in a
potent dual inhibitor (Ki values for both fXa and thr = 2 nM)
endowed with good in vitro anticoagulant activity (1.5 × PT =
0.54 μM) and oral bioavailability. 2-Chloronaphtalene was
also introduced as P1 neutral moiety (e.g., 116) [145,146].
Edoxaban 9 (DU-176b, Daiichi Sankyo) is an oral fXa
inhibitor showing Ki value of 0.6 nM, 10,000-fold more
selective for fXa than for thr. Daiichi Pharmaceuticals reported
several series of fXa inhibitors incorporating chlorotiophene,
chlorobenzene, chloropyridine and chloroindole as P1 binding
moieties and, in most cases, 5-methyl(or isopropopyl)-4,5,6,
7-tetrahydrothiazole[5,4-c]pyridine as P4 group. One patent
reported N-formyl (or acetyl) piperidine-3,4-diamide
derivatives [147]. The water-soluble compound 117 exhibited
good fXa inhibitory potency (IC50 = 0.9 nM) and anticoagulant properties (2 × PT in human plasma = 0.14 μM), as
well as oral bioavailability in monkeys (AUC = 899 ng·h/ml).
Using diversely substituted 3-aminobenzoic acid as central
scaffold, a wide series of fXa inhibitors was obtained [148],
the most active compound in this series being 118 (fXa
IC50 = 0.51 nM). Change in the fluorine atom position
led to marked loss of activity, and the carboxylic group
emerged as important element. As for compounds bearing
chloropyridine as the P1 moiety, in vitro IC50 values were
reported only for 119 and 120 (2.2 and 1.6 nM, respectively).
These compounds displayed good anticoagulant properties (2 × PT in human plasma = 0.26, 0.25 and 0.50 μM,
respectively) and pharmacokinetics after oral administration
in monkey.
Among fXa inhibitors of Daiichi Sankyo, compound 121
(IC50 = 2.2 nM) [149] deserves mention. Substitution of
chloropyridine with chlorobenzene moiety causes 60% loss of
the inhibitory activity. The replacement of chlorine atom in the
central ring with a methoxy group did not produce any significant biological effect. In contrast, fluorination at 3-position
of the piperidine ring slightly increased potency, as shown
by the IC50 value of compound 122 (1.8 nM), whereas a carboxyl group on the central phenyl ring doubled the inhibitory
potency (123, fXa IC50 = 1.1 nM). Novel fXa inhibitors
were identified among compounds built up using 3-amino-4(2-carboxyethyl)benzoic acid as the central scaffold, such as 124
and 125 (fXa IC50 = 0.38 and 0.39 nM, respectively) [150].
Very recently, Daiichi Sankyo Co. filed a patent describing
synthesis of orally available potent factor Xa inhibitors [151].
Their disclosures include compounds bearing 5-chloroindole
and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine groups
as suitable P1 and P4 moieties, respectively. A series of
(piperazin-1-yl)sulfonyl derivatives were provided, which
displayed high fXa inhibition potency, as exemplified by
Expert Opin. Ther. Patents (2009) 19(11)
31
1565
Novel factor Xa inhibitors: a patent review
O
OH
O
S
N
N
NH
N
S
HN
N
O
F
O
H
N
NH
O
N
NH
O
O
S
S
Cl
Cl
117
118
O
O
S
S
N
N
NH
NH
N
N
O
H
N
O
H
N
N
N
NH
NH
O
O
O
O
N
N
Cl
Cl
119
120
F
N
N
NH
NH
O
O
Cl
Cl
O
O
HN
HN
N
N
Cl
Cl
122
121
1566
Expert Opin. Ther. Patents (2009) 19(11)
32
de Candia, Lopopolo & Altomare
O
OH
N
O
NH
S
N
NH
O
N
O
O
O
O
NH
HN
Cl
HO
N
Cl
Cl
123
124
O
S
N
NH
N
O
O
NH
CF3
HO
Cl
125
compound 126 (Ki = 5 nM), but with unsatisfactory oral
bioavailability [152]. The replacement of piperazine with
1,2-cyclohexyldiamine led to less potent fXa inhibitors, whereas
better results were achieved with the diamide derivatives cis-127
(Ki = 41 nM) and trans-128 (Ki = 13 nM). Ring size showed
significant effect on potency [153].
Although less potent than the trans isomer 128, cis-127
showed better anticoagulant activity. Even more the dimethylcarbamoyl derivative 129, with a given stereochemistry, enhanced
fXa inhibition and anticoagulant activity (Ki = 5.1 nM,
2 × PT = 0.9 μM).
AstraZeneca contributed to the discovery of novel fXa inhibitors with four patents. Two patents disclosed compounds 130
(fXa IC50 = 18 nM) and 131 (fXa IC50 = 0.5 nM) [154,155].
Another series incorporates piperidine instead of the phenyl
ring; this is exemplified by compounds 132 (IC50 = 2.3 nM) [156]
and 133 (IC50 = 4.8 nM) [157].
Three patents from Merck described pyrazole carboxamide
derivatives bearing benzylamine (134) or benzamide (135 – 137)
groups as P1 moieties, and various basic and nonbasic
pyrrolidine-, imidazolidine- and 1,3,4-thiadiazole-containing
P4 moieties [158-160]. These compounds were shown to serve
as dual fXa/TF:FVIIa inhibitors, as specified by compound 134 (fXa IC50 = 9.6 nM; TF:FVIIa IC50 = 23 nM).
One patent claimed disclosure of proline derivatives, exemplified by compounds 138 and 139 [161], without furnishing
the respective biological data. Further developments of
previously registered glycine-based fXa inhibitors were also
described [162].
In previous patents, Eli Lilly & Co. disclosed LY-517717 (8)
as a clinical candidate [29]. Further patents claimed a stable
crystalline salt of LY-517717 [163], additional modifications
to anthranilamide-based fXa inhibitors, as exemplified by
compound 140 (fXa Kass = 407 × 106 l/mol) [164] and novel
pyridine-3,4-diamine derivatives, such as compound 141 [165].
Takeda Pharmaceutical Co. reported several fXa inhibitors
containing piperidine as central scaffold and 2-chloronaphtalene
as S1 binding moiety. A recent disclosure deals with sustained
Expert Opin. Ther. Patents (2009) 19(11)
33
1567
Novel factor Xa inhibitors: a patent review
N
N
S
O
N
N
S
O
N
HN
HN
O
HN
N
O
S
O
NH
Cl
Cl
126
N
127
O
S
S
O
N
O
N
N
HN
HN
N
HN
HN
O
O
HN
HN
Cl
Cl
128
129
release preparations containing fXa inhibitors like compound
142 [166-168]. Additional modifications were accomplished by
replacing piperidine with piperazine; compound 143 (fXa
IC50 = 2.1 nM) exemplifies this series.
Among the anthranilamide-based compounds, betrixaban
(PRT-054021, 10) was found to be an orally available fXa
inhibitor (Ki = 0.117 nM), which has been selected as clinical
candidate [135]. Portola Pharmaceuticals has filed two previous
patents claiming preparation of amino acid (e.g., glycine,
phenylglycine), urea [169] and thiourea [170] derivatives. Most of
their disclosures include compounds bearing chlorophenyl
or bromophenyl groups as P1 elements, as exemplified by
compounds 144 and 145, respectively (fXa IC50 ≤ 100 nM).
Sulfonyl urea derivatives, specified by compound 146, were
claimed as agents effective in inhibiting ADP-dependent
human blood platelet aggregation [171].
1568
Pfizer has registered a patent reporting preparation of
the chiral 5-methyl-4,5-dihydropyrazole-based fXa inhibitor
147 [172], in which the S enantiomer (IC50 = 0.982 nM) was
claimed as much more potent inhibitor than the R enantiomer
(0.141 μM). Preparation of polymorphic crystalline forms of
the (2R,4R)-1,2-pyrrolidine carboxamide fXa inhibitor (148),
known as eribaxaban [173], has been described by WarnerLambert (Morris Plains, New Jersey, US) in a patent [174]
that additionally reports suitable pharmaceutical dosage.
Aventis Pharma, which merged with Sanofi in 2004, has
contributed to the development of novel fXa inhibitors during
the period 2000 – 2005 [29]. A major outcome of the efforts
of the Aventis group was the discovery of otamixaban (2,
fXa K i = 0.4 nM). A recent patent [175] deals with
aminosulfonylethyl-based compounds, as exemplified by
compound 149 (Ki = 5 nM).
Expert Opin. Ther. Patents (2009) 19(11)
34
de Candia, Lopopolo & Altomare
N
N
N
N
N
N
O
O
N
N
SO2
N
NH
O
SO2
O
NH
Cl
Cl
130
131
O
O
O
OH
N
N
N
N
N
N
N
N
N
N
SO2
O
SO2
O
O
NH
NH
Cl
Cl
133
132
Other companies have contributed to the advances in the
field in recent years. Among them, Legochem Biosciences
(Daejeon, KR) has reported various rivaroxaban-like compounds (e.g., 150 with Ki = 0.39 nM) [176,177]. Tanabe Seiyaku
Co. (Osaka, JP) has used, among others, benzofuran as central
scaffold (151, IC50 = 0.8 nM) [178] and described 3-chloroanthranilamide derivatives (152, IC50 = 2.5 nM) [179]. Astellas
Pharma disclosed anthranilamide derivatives, exemplified by
compound 153 (fXa IC50 = 6.7 nM) and the glucuronic acid
derivative 154 [180]. Mochida Pharmaceutical Co. (Gotemba,
Shizuoka, JP) investigated two different families of spiro-tricyclic
and tetracyclic perhydroimidazo[1,2-a]pyrazine derivatives
with general structure 155 [181-184]. Compound 156 (fXa
Ki = 0.4 nM) is representative of this family. Schebo Biotech
has described preparation and suitable pharmaceutical compositions of new fXa inhibitors belonging to oxazolidinone (157),
pyrazolo[3,4-c]pyridine (158), anthranilamide (159) and
salicylamide (160) series [66,67]. The preparations of deuterated
rivaroxaban and related pharmacokinetic study in rats [185],
as well as deuterium-enriched apixaban [186], have been also
reported in the patent literature.
5.
Expert opinion
New anticoagulants that do not need frequent monitoring
or dose adjustment are required for VTE treatment and
stroke prevention in patients with AF. Among them, drugs
that inhibit fXa are attractive options. As fXa inhibitors prevent the generation of new thrombin, without affecting its
basal level that ensures primary haemostasis, their use may
overcome bleeding, that is, a limitation of current oral
antithrombotic therapy.
The first generation of direct fXa inhibitors (the so-called
xabans), which relied upon a benzamidine group as S1 binding
moiety, exhibited high clearance and limited oral bioavailability. These limitations have been successfully addressed
through the replacement of the benzamidine moiety with
less basic bioisoster or nonpolar neutral P1 elements. Indeed,
fXa inhibitors under the most advanced stage clinical trials,
namely rivaroxaban, apixaban and edoxaban, bear different
lipophilic non-amidine groups as P1 substituents.
Numerous oral, direct fXa inhibitors are currently at various
stages of clinical development. The selective inhibitors that
Expert Opin. Ther. Patents (2009) 19(11)
35
1569
Novel factor Xa inhibitors: a patent review
S
NH
N
CF3
NH
O
N
N
CF3
NH
N
N
N
O
Cl
O
H 2N
H2N
134
135
CN
N
NH
S
HN
N
CF3
NH
N
CF3
NH
N
O
N
N
N
O
N
O
O
H2N
H2N
136
137
O
O
O
N
O
NH
O
N
NH
N
O
N
O
N
S
HN
S
S
Cl
Cl
139
138
1570
Expert Opin. Ther. Patents (2009) 19(11)
36
de Candia, Lopopolo & Altomare
H2N
F
O
N
O
O
O
O
N
N
HN
F
N
H
O
HN
O
O
NH
N
O
Cl
140
141
O
O
O
N
N
N
N
N
N
N
HN
HO
O
SO2
HO
Cl
SO2
Cl
142
143
HN
N
NH
NH
N
N
O
NH
O
NH
S
O
NH
NH
Br
Cl
144
145
Expert Opin. Ther. Patents (2009) 19(11)
37
1571
Novel factor Xa inhibitors: a patent review
O
F
N
F
NH
O
N
H
N
N
H
N
O
O
N
O
N
H
HN
O
NH
O
S
O
S
Cl
Cl
146
147
O
F
O
N
NH
N
O
O
NH
Cl
148 Eribaxaban
recently reached the clinic no longer contain highly charged
groups, such as amidine and carboxylic acid groups. They incorporate neutral (e.g., rivaroxaban, apixaban) or less basic amidine
mimics (e.g., edoxaban, betrixaban), which lead to significant
improvement in oral bioavailability. Rivaroxaban, apixaban and
edoxaban are the furthest advanced in their development
programs, but other low molecular weight direct fXa inhibitors,
such as YM-150, LY-517717, betrixaban, TAK-442, entered
Phase II clinical trials. Pivotal Phase III studies and several
Phase II trials have established the efficacy and safety of these fXa
inhibitors for the prevention of VTE after orthopedic surgical
interventions and/or for the treatment of VTE, supporting on
the other hand the potential for stroke prevention in patients with
AF. The clinical development of new anticoagulants, including
the direct fXa inhibitors, follows the well-established strategy
of dose-ranging and registration studies in major orthopedic
surgery, prior to development in arterial indications. Based
on data from clinical trials, the availability of new oral fXa
inhibitors is expected to have a great impact on the AF-related
1572
stroke prevention segment of the market, in which the use
of warfarin should become obsolete [42].
Besides novel selective fXa inhibitors, direct thrombin inhibitors, such as dabigatran ethexilate, with better therapeutic
windows and ease-of-use than the existing anticoagulants, which
can conveniently replace heparins and vitamin K antagonists
(i.e., warfarin) in the prophylaxis and treatment of thrombotic disorders, are currently being developed. It remains to
be established which is a better target between fXa and thr.
To address this question direct comparison trials are needed.
Although the new anticoagulants exhibited favorable safety
profiles, there is, however, the need of monitoring them for
unexpected adverse effects.
As far as the future developments are concerned,
> 100 patents filed between 2006 and April 2009, examined
in this review, highlight the variety among the P1 and P4 moieties, showing that the majority of the newly synthesized fXa
inhibitors contains neutral lipophilic groups as P1 moieties.
Privileged non-amidine P1 groups are 2-chlorothiophene,
Expert Opin. Ther. Patents (2009) 19(11)
38
de Candia, Lopopolo & Altomare
O
S
N
N
N
N
N
O
S
O
N
O
O
HN
HN
O
O
S
S
Cl
149
Cl
150
OH
O
O
O
O
O
O
N
HN
N
HN
Cl
O
O
NH
O
N
NH
N
Cl
Cl
151
152
HO
OH
O
O
HO
O
HO
O
O
N
O
OH
O
HN
N
HN
O
NH
O
N
NH
N
Cl
Cl
153
154
Expert Opin. Ther. Patents (2009) 19(11)
39
1573
Novel factor Xa inhibitors: a patent review
O
O
N
N
N
N
N
(
O
)n
Y
O
R2
O
S
N
O
N
N
R1
S
O2
N
NH
R3
O
Cl
155
O
156
O
O
O
O
N
NH2
N
O
O
N
N
H
N
N
N
O
O
O
S
O
Cl
157
158
O
H2N
HN
O
H2N
HN
NH
O
O
O
O
O
O
NH
NH
O
N
N
Cl
Cl
159
1574
160
Expert Opin. Ther. Patents (2009) 19(11)
40
de Candia, Lopopolo & Altomare
3-chloropyridine, chlorobenzene, methoxybenzene and 5-chloro1H-indole. While the central core may largely vary, including
oxazolidine, pyrazole, piperazinone, anthranilamide, indole, indazole, cyclic diamine and others, there are a number of recurrent
P4 substituents, among which pyridine-2(1H)-one, piperidin2-one, morpholin-2-one, fused piperidines and benzazepines
emerge as the most preferred ones. Many combinations of P1
and P4 groups on suitable scaffolds have led to the disclosure
of a number of fXa inhibitors with high potency, selectivity
and oral bioavailability, and the results from Phase II and
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An excellent review that highlights the
current pharmacology and the most
recently published data from clinical
••
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.
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including factor Xa inhibitors.
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a highly potent, selective, and orally
bioavailable inhibitor of blood coagulation
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Wong PC, Pinto DJ, Knabb RM.
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Affiliation
Modesto de Candia1 PhD,
Gianfranco Lopopolo2 & Cosimo Altomare†3
†Author for correspondence
1Assistant Professor,
University of Bari,
Dipartimento Farmaco-Chimico,
Via E. Orabona 4,
I-70125 Bari, Italy
2PhD Student,
University of Bari,
Dipartimento Farmaco-Chimico,
Via E. Orabona 4,
I-70125 Bari, Italy
3Full Professor of Medicinal Chemistry,
Head of the Department,
University of Bari,
Dipartimento Farmaco-Chimico,
Via E. Orabona 4,
I-70125 Bari, Italy
Tel: +39 080 5442781; Fax: +39 080 5442230;
E-mail: [email protected]
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