Structure-activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties

Article abstract of DOI:10.1016/j.bmcl.2008.03.092

Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit a

Full text of DOI:10.1016/j.bmcl.2008.03.092

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2845–2849
Structure–activity relationships of anthranilamide-based factor
Xa inhibitors containing piperidinone and pyridinone P4 moieties
James R. Corte,a,* Tianan Fang,a Donald J. P. Pinto,a Wei Han,a Zilun Hu,a
Xiang-Jun Jiang,a Yun-Long Li,a,ꢀ Jolicia F. Gauuan,b Mark Hadden,b Darren Orton,b
Alan R. Rendina,a Joseph M. Luettgen,a Pancras C. Wong,a Kan He,a Paul E. Morin,a
Chong-Hwan Chang,a Daniel L. Cheney,a Robert M. Knabb,a
Ruth R. Wexlera and Patrick Y. S. Lama
aBristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543, USA
bAlbany Molecular Research, Inc., 21 Corporate Circle, PO Box 15098, Albany, NY 12212, USA
Received 1 March 2008; revised 22 March 2008; accepted 31 March 2008
Available online 8 April 2008
Abstract—Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent,
selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit
arteriovenous-shunt (AV) thrombosis model.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Thromboembolic disorders, such as deep vein thrombo-
sis, pulmonary embolism, myocardial infarction, and
stroke, are the leading cause of mortality and disability
in the industrialized world. Warfarin (Coumadinꢁ), the
only oral anticoagulant on the market, is effective for the
prevention and treatment of thromboembolic disorders.
However, due to the narrow therapeutic window and
highly variable dose response among individuals (food
interactions, drug–drug interactions, genetic polymor-
phisms), careful monitoring is required to provide an
antithrombotic effect while minimizing the risk of severe
bleeding.1 There is a need for safer, more efficacious oral
anticoagulants.
causing a significant increase in bleeding.2 As a result,
research on small molecule fXa inhibitors is a major
area of interest for the pharmaceutical industry.3
Work from our laboratories led to the discovery of the
clinical candidate apixaban (BMS-562247, Fig. 1).4 This
potent, selective, and orally bioavailable fXa inhibitor
contained the novel, neutral, phenyl piperidinone P4
group. As part of our research program to explore struc-
turally diverse fXa inhibitors as potential back-up can-
didates, we introduced the phenyl piperidinone P4
moiety into the anthranilamide scaffold which gave 2,
a single digit nanomolar fXa inhibitor (Fig. 1). Next,
One approach to address this unmet medical need has
focused on selective factor Xa (fXa) inhibitors. Factor
Xa, a trypsin-like serine protease, is a key enzyme lo-
cated at the junction between the intrinsic and extrinsic
pathways of the coagulation cascade. Experimental evi-
dence suggests that selective fXa inhibitors may offer a
safe profile by preventing thrombus formation without
NH2
O
O
O
N
H
O
N
N
N
N
HN
N
O
N
O
OMe
Cl
2 (piperidinone) 3 (pyridinone)
apixaban (1)
BMS-562247
fXa Ki = 1.2 nM
fXa Ki = 0.14 nM
PT2x = 4.6 μM
PT2x = 2.6 μM
Keywords: Factor Xa; Anthranilamide.
*
fXa Ki = 0.08 nM
Corresponding author. Tel.: +1 609 818 5806; fax: +1 609 818
3331; e-mail: james.corte@bms.com
Present address: Incyte, Wilmington, DE 19880, USA.
PT2x = 3.8 μM
ꢀ
Figure 1. Apixaban and anthranilamides 2 and 3.
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.092

2846
J. R. Corte et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2845–2849
Table 2. P1 linker modifications
we discovered that incorporation of the unsaturated ver-
sion of this P4 group, the phenyl pyridinone,5 gave 3, a
potent fXa inhibitor with similar in vitro activity to
apixaban. In this letter, we describe the SAR of anthra-
nilamide-based fXa inhibitors containing these piperidi-
none and pyridinone P4 moieties. Subsequent to this
work, other fXa inhibitors containing phenyl piperidi-
none and phenyl pyridinone P4 groups were described
in the literature.6 It should also be noted that anthra-
nilamide-based fXa inhibitors have been previously re-
ported by several groups.7–10
O
O
N
H
X
N
HN
N
Cl
Compound
X
fXa Kia (nM)
PTb (EC2·, lM)
12
13
14
–CH2–
–CH(CH3)–
–SO2–
0.62
59
6.7
c
—
c
—
5.5
Since the phenyl pyridinone moiety proved to be a via-
ble P4 group in the anthranilamide core, we decided to
explore the remaining regions of the molecule in order
to optimize the in vitro and in vivo properties of this ser-
ies. Our initial efforts focused on the exploration of the
P1 group (Table 1). The position of the chlorine substi-
tuent was very important for binding in the S1 pocket.
The removal of the chlorine gave the unsubstituted pyr-
idine 4 which resulted in >20-fold loss in activity.
Replacing the chloro with fluoro (6) led to a 7-fold loss
in fXa activity. Though the isosteric methyl derivative
(7, fXa Ki=0.58 nM) showed a minor drop in activity,
the trifluoromethyl derivative (8) exhibited a significant
(>2500-fold) loss. The 5-Cl-Pyrimidin-2-yl (9) exhibited
a 9-fold loss in fXa Ki activity, however, the 4-Cl-phenyl
(10) was equivalent to 3, both in terms of inhibitory
activity in the fXa assay and potency in the in vitro clot-
ting assay. We recognized that the P1 amide bond may
be hydrolyzed in vivo generating potentially mutagenic
aniline metabolites. Since the 2-amino-5-chloropyridine
fragment was inactive in our Ames and MTT cytotoxic-
ity assays,12 it became our preferred P1 group for this
series.
a Ki values were obtained from purified human enzyme and were
averaged from multiple determinations (n = 2), as described in Ref.
11.
b PT (prothrombin time) in vitro clotting assay was performed in
human plasma as described in Ref. 11.
c Not tested.
lene (12) led to only a 5-fold drop in activity but unfor-
tunately the EC2· value in the clotting assay was high.
Branching at the benzylic position (13) resulted in a
more dramatic loss in fXa activity. Even though the sul-
fonamide linker (14) led to a 40-fold loss in activity, it
was still a single digit nanomolar fXa inhibitor.
˚
An X-ray structure of 14 bound to fXa (1.6 A resolu-
tion, R-value = 0.26, Fig. 2) was obtained.13 The overall
P1–P4 trajectory is similar to that described previously.9
The P1 chloro is positioned above Y228, and there is a
˚
weak to moderate hydrogen bond (3.2 A) between the
P1 sulfonamide N–H and the carbonyl of G218 and a
˚
strong hydrogen bond (2.7 A) between the P4 amide
N–H and the carbonyl of G216. The pyridinone, which
is orthogonal to the inner phenyl ring, forms an edge to
face interaction with W215 and is appropriately sand-
wiched between Y99 and F174.
As an alternative strategy to address the potential
hydrolysis of the P1 amide, we investigated additional
P1 linkers (Table 2). Reducing the carbonyl to a methy-
The SAR of the P4 linker moiety is highlighted in Table
3. As was observed in the P1 amide linker, the conver-
sion of the P4 amide carbonyl to methylene (15) resulted
in a 7-fold loss in fXa activity and a significant drop in
the in vitro clotting assay. Surprisingly, the introduction
of sulfonamide (16) led to a significant loss in activity.
Table 1. P1 modifications
O
N
H
O
HN
R
O
N
Compound
R
fXa Kia
(nM)
PTb
(EC2·, lM)
3
4
5-Cl-Pyridin-2-yl
Pyridin-2-yl
Pyridin-3-yl
0.14
3.0
2.6
c
—
—
c
5
43
1.0
6
5-F-Pyridin-2-yl
5-Me-Pyridin-2-yl
5-CF3-Pyridin-2-yl
5-Cl-Pyrimidin-2-yl
4-Cl Phenyl
2.8
2.7
7
0.58
1560
1.3
c
8
—
9
3.2
3.5
10
11
0.21
4.2
c
3-Cl Phenyl
—
a Ki values were obtained from purified human enzyme and were aver-
aged from multiple determinations (n = 2), as described in Ref. 11.
b PT (prothrombin time) in vitro clotting assay was performed in
human plasma as described in Ref. 11.
c Not tested.
Figure 2. X-ray crystal of 14 in factor Xa.

J. R. Corte et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2845–2849
2847
Table 3. P4 linker modifications
Table 5. Substituted anthranilamide cores with phenyl piperidinone P4
5
3
O
R
Y
N
O
N
O
H
H
HN
N
O
N
HN
N
O
N
Cl
Cl
Compound
Y
fXa Kia (nM)
PTb (EC2·, lM)
Compound
R
H
fXa Kia
(nM)
PTb
(EC2·, lM)
3
15
16
–C(O)–
–CH2–
–SO2–
0.14
1.1
2.6
>20
2
23
24
25
26
27
28
29
30
1.2
2.0
4.6
9.6
3.8
1.3
11
c
—
7670
5-MeSO2NH
5-CN
5-Cl
a Ki values were obtained from purified human enzyme and were
averaged from multiple determinations (n = 2), as described in Ref.
11.
0.45
0.33
0.14
0.19
0.057
0.047
0.065
5-Br
5-Me
b PT (prothrombin time) in vitro clotting assay was performed in
2.8
1.5
4.0
1.0
3-OMe, 5-Cl
3-OH, 5-Cl
3-O(CH2)2NMe2, 5-Cl
human plasma as described in Ref. 11.
c Not tested.
a Ki values were obtained from purified human enzyme and were
averaged from multiple determinations (n = 2), as described in Ref.
11.
Next, we modified the anthranilamide scaffold.14 Our
earlier work in the pyrazole-5-carboxamide series re-
vealed that a methyl substituent at the C3 position of
the pyrazole provided a 10-fold increase in fXa binding
by interacting with a small lipophilic pocket above the
S1 pocket near the C191–220 disulfide bridge.11,15 Mod-
eling suggested that substitution at C5 of the phenyl core
could access this pocket. A number of C5-substituted
phenyl cores containing the phenyl pyridinone P4 group
were synthesized (Table 4).
b PT (prothrombin time) in vitro clotting assay was performed in
human plasma as described in Ref. 11.
and 5-Me (27) gave a 4-fold and 6-fold increase in
potency, respectively. Gratifyingly, the 3-OMe, 5-Cl
phenyl (28) provided an additional enhancement in po-
tency giving a 57-pM fXa inhibitor. Since the conversion
of the 3-OMe (28) to 3-OH (29) did not affect fXa activ-
ity, we used the phenol as a handle to introduce solubi-
lizing groups. For example, the 5-chloro-3-N,N-
dimethyl ethyl derivative (30) was equipotent to 28
and showed a >45-fold improvement in aqueous solubil-
ity (cf. compound 30, amorphous, 912 lg/mL, with com-
pound 28, amorphous, 19 lg/mL; measured by a
thermodynamic equilibrium aqueous solubility assay at
pH 6.5 in a 25-mM potassium phosphate buffer).
Small groups like 5-Cl (19) and 5-Me (20) gave a 2-fold
and 5-fold increase in potency, respectively. Introduc-
tion of the 3-OMe, 5-Cl phenyl core, which was origi-
nally developed by researchers at Berlex,9 gave 22 as a
13-pM fXa inhibitor with an excellent PT value. We ob-
served a similar enhancement in potency when these
substituted phenyl cores and the phenyl piperidinone
P4 were combined (Table 5). Groups like 5-Cl (25)
A brief investigation of the phenyl portion of the phenyl
pyridinone group was undertaken (Table 6). Replacing
the phenyl ring with the pyridine analogue (31) showed
Table 4. Substituted anthranilamide cores with phenyl pyridinone P4
5
3
O
R
N
O
H
HN
N
O
N
Table 6. P4 modifications
Cl
O
O
R
Cl
N
H
Z
O
HN
O
N
Compound
R
H
fXa Kia (nM)
PTb (EC2·, lM)
N
3
17
18
19
20
21
22
0.14
0.12
2.2
2.6
c
5-MeSO2NH
5-CN
5-Cl
—
Cl
>20
6.4
2.0
2.6
1.4
0.060
0.028
0.14
0.013
Compound
R
Z
fXa Kia
(nM)
PTb (EC2x, lM)
5-Me
3-OMe
3-OMe, 5-Cl
31
32
H
F
N
CH
0.24
0.005
3.0
1.6
a Ki values were obtained from purified human enzyme and were
averaged from multiple determinations (n = 2), as described in Ref.
11.
a Ki values were obtained from purified human enzyme and were
averaged from multiple determinations (n = 2), as described in Ref.
11.
b PT (prothrombin time) in vitro clotting assay was performed in
human plasma as described in Ref. 11.
b PT (prothrombin time) in vitro clotting assay was performed in
human plasma as described in Ref. 11.
c Not tested.

2848
J. R. Corte et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2845–2849
Table 7. Dog pharmacokinetic profilea
O
O
O
c, d
a or b
O
O
Compound
Cl
(L/h/kg)
t1/2
Vdss (L/kg)
F (%)
Cl
O
O
(po) (h)
N
N
I
Apixaban (1)
0.02
0.67
0.70
0.30
0.80
5.8
0.2
58
22
28
31
32
0.70
1.5
0.62
1.3
99
44
74
18
33
34 (piperidinone)
35 (pyridinone)
36 (piperidinone)
37 (pyridinone)
1.6
0.70
0.81
2.6
Scheme 1. Reagents and conditions: (a) d-valerolactam, CuI, K2CO3,
N,N0-dimethyl ethylene diamine, toluene, 100 ꢂC, 70%; (b) pyridine-2-
one, CuI, K2CO3, 1,10-phenanthroline, DMSO, 110 ꢂC, 17–82%; (c)
NaOH, MeOH, H2O, 84–96%; (d) SOCl2, cat. DMF, 1,2-dichloroeth-
ane, reflux, quantitative.
a Compounds were dosed in an N-in-1 format as described in Ref. 4.
Doses ranged from 0.02 to 0.5 mg/kg for iv and po.
a 20-fold loss in activity. Previously, we have shown that
the substitution of a fluoro substituent on the phenyl
ring in the P4 group enhanced fXa activity in the pyra-
zole 5-carboxamide series.15 Thus, the introduction of
the 3-fluoro substituent on the P4 phenyl ring led to
32 (fXa Ki = 5 pM), the most potent anthranilamide
derivative in our study.
thrombus formation by 34%, 70%, and 80%, respec-
tively. The calculated ID50 of 28 was 0.97 lmol/kg/h
and it was comparable to that of apixaban
(ID50 = 2.4 lmol/kg/h) in this model.
Representative examples of the synthesis of the piperid-
inone and pyridinone P4 groups are described in Scheme
1. Copper-catalyzed amidation of phenyl iodide 33 with
either d-valerolactam or pyridin-2-one, according to
Buchwald’s protocol,20 yielded piperidinone 34 and
pyridinone 35. The esters were hydrolyzed to the car-
boxylic acids which were then converted to the acid
chlorides 36 and 37.
The pharmacokinetics of compounds 22, 28, 31, and 32
were investigated in dogs and the data for apixaban are
included for comparison (Table 7). These anthranila-
mides have low to moderate clearance and good oral
bioavailability. However, due to higher clearance than
apixaban, these compounds have a shorter half-life.
Based on good in vitro potency in the fXa assay, good
oral bioavailability, and excellent selectivity against
related serine proteases (>10,000-fold against trypsin,
plasma kallikrein, activated protein C, factor IXa, factor
XIa, thrombin, factor VIIa, chymotrypsin, urokinase,
plasmin, and tPA), compound 28 was chosen for further
evaluation in mechanistic16a and in vivo studies. As
expected for reversible, active site inhibitors, 28 was
competitive versus a tripeptide substrate (37 ꢂC Ki is
0.2 nM)16b with a rapid onset of inhibition,17 but exhib-
ited mixed-type inhibition versus the physiological sub-
strate, prothrombin, which interacts with fXa
primarily at exosites.18 An advantage of this mechanism
is that 28 is a potent inhibitor at both low (prothrombin-
ase 37 ꢂC Ki for free E is 0.6 nM) and saturating (Ki for
ES is 1.7 nM) physiological levels of prothrombin. In
the rabbit arteriovenous-shunt (AV) thrombosis mod-
el,19 compound 28 at 0.3, 1.0, and 3.0 mg/kg/h inhibited
The preparation of the anthranilamide analogues is
exemplified by the synthesis of 28 (Scheme 2). Reacting
the substituted aniline 38 with the P4 acid chloride 36
followed by the introduction of the 2-amino-5-chloro-
pyridine, according to Weinreb’s procedure,21 gave 28.
Cleavage of the methyl ether with BBr3 provided 29
and subsequent alkylation with 2-chloro-N,N-dimethyl-
ethyl amine under basic conditions afforded 30.
Introduction of either the phenyl piperidinone or the
phenyl pyridinone P4 groups into the anthranilamide
scaffold led to potent fXa inhibitors. Optimization of
this series led to compound 28, a potent, selective, and
orally bioavailable fXa inhibitor which displayed com-
parable efficacy to apixaban in the rabbit arteriove-
nous-shunt (AV) thrombosis model. However,
compound 28 had a shorter half-life compared to
apixaban.
R
Cl
O
Cl
O
Cl
O
O
O
a
b
N
H
O
N
H
O
NH2
MeO
O
N
HN
O
N
MeO
O
N
38
39
Cl
28 R =Me
c
d
29 R = H
30 R = (CH2)2N(CH3)2
Scheme 2. Reagents and conditions: (a) acid chloride 36, pyridine, dichloromethane, 0 ꢂC–rt, 83%; (b) 5-Cl-2-NH2-pyridine (10 equiv), AlMe3
(9.8 equiv), 1,2-dichloroethane, then 39, rt–40 ꢂC, 26–59%; (c) BBr3, dichloromethane, 0 ꢂC–rt, 29%; (d) KOH, DMSO (or NaH, DMF),
Cl(CH2)2N(CH3)2ÆHCl, 75ꢂC,8%.

J. R. Corte et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2845–2849
2849
10. (a) Zhang, P.; Bao, L.; Zuckett, J. F.; Jia, Z. J.; Woolfrey,
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Acknowledgments
The authors thank Jeffrey Bozarth, Frank Barbera, Ka-
ren Hartl, Diane Normandin, and Tracy Bozarth for
in vitro work, Carol A. Watson and Earl J. Crain for
in vivo work, and Dr. Steven Sheriff for post-refinement
analysis of the X-ray data and for depositing the coordi-
nates in the PDB.
References and notes
12. Unpublished results from our laboratories. For the
mutagenicity of p-chloroaniline see: Zeiger, E. Environ.
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13. PDB deposition number is 3CEN.
14. The central phenyl ring was replaced with all of the
possible pyridine ring systems containing the phenyl
pyridinone P4. These derivatives were equivalent to or
showed a 2- to 3-fold loss in fXa activity compared to 3.
Saturated carbocyclic cores were also investigated, see
US2006/74103.
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