Structure-activity relationship and pharmacokinetic profile of 5-ketopyrazole factor Xa inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.11.040

Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker

Full text of DOI:10.1016/j.bmcl.2007.11.040

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 749–754
Structure–activity relationship and pharmacokinetic profile
of 5-ketopyrazole factor Xa inhibitors
Jeffrey G. Varnes, Dean A. Wacker,* Donald J. P. Pinto, Michael J. Orwat,
Jay P. Theroff, Brian Wells, Robert A. Galemo, Joseph M. Luettgen,
Robert M. Knabb, Steven Bai, Kan He, Patrick Y. S. Lam and Ruth R. Wexler
Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08542-5400, USA
Received 12 October 2007; revised 8 November 2007; accepted 12 November 2007
Available online 17 November 2007
Abstract—Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa)
inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido lin-
ker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting
ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conver-
sion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyraz-
ole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of
razaxaban and improved selectivity over thrombin.
ꢀ 2007 Elsevier Ltd. All rights reserved.
A direct inhibitor of fXa is an attractive therapeutic tar-
get for prevention and treatment of thrombotic dis-
eases.1 Since small quantities of fXa can lead to the
production of large quantities of thrombin, the agent
responsible for catalyzing the conversion of fibrinogen
to fibrin and activating platelets during clot formation,
inhibition of fXa is highly efficient.2 Inhibitors of fXa
are also expected to have a wider therapeutic window
compared to thrombin inhibitors in a clinical setting.3
in we describe an alternative series that replaces the car-
boxamido linker between the pyrazole and proximal
phenyl group of the razaxaban scaffold with a ketone
moiety, thus obviating potential formation of aniline
metabolites altogether.
Initial leads for the ketone series are presented in Table 1.
The effects of both methylene substitution (R1) and fluo-
rine incorporation at the 20-position of the proximal
phenyl ring (R2) were explored. Sulfone 1 and sulfon-
amide 2 were 2- to 3-fold less active than razaxaban in
terms of fXa binding affinity but demonstrated better
selectivity over trypsin. Anticoagulation activity in both
prothrombin time (PT) and activated partial thrombo-
plastin time (aPTT) assays was low and permeability
was negligible in the Caco-2 assay for 2. Fluorine incor-
poration was attempted to improve fXa affinity, in vitro
anticoagulation activity, and permeability for these
compounds.8a Compared to their non-fluorinated ana-
logs, binding affinity for fXa was increased by 10-fold
for 20-fluoro sulfone 3 and 3-fold for 20-fluoro sulfon-
amide 4. The sulfonamide (4) was also more active in
the anticoagulation assays and exhibited greater perme-
ability than its desfluoro analog 2. To determine the ef-
fect of substitution alpha to the ketone, we methylated
several compounds. This methylation alpha to the car-
bonyl, as exemplified by comparing 8 with 4, was found
Recently we described two new series of pyrazole-based
fXa inhibitors as part of our efforts to further optimize
our clinical candidate razaxaban.4 While the biaryl-ani-
line P4 moiety of razaxaban tested negative in the Ames
assay and was not observed in vivo, both series were de-
signed to eliminate possible formation of a potentially
mutagenic primary biarylaniline.5 The tetrahydropyraz-
olo-pyridinone series culminated in BMS-740808, which
demonstrated high affinity for fXa and favorable in vivo
pharmacokinetic and antithrombotic profiles.6 The ind-
oline series produced potent compounds that had good
clotting activity in vitro but poor bioavailability.7 Here-
Keywords: Factor xa; Anticoagulant.
*
Corresponding author. Tel.: +1 215 968 2496; e-mail: dean.wacker@
bms.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.040

750
J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 749–754
OH
N
F3C
F
F3C
N
H
N
N
N
N
N
N
N
N
O
O
NH2
NH2
O
O
N
N
razaxaban (BMS-561389, DPC906)
FXa Ki = 0.19 nM (PTIC2x = 1.3 μM)
Thrombin Ki = 540 nM
BMS-740808
FXa Ki = 0.03 nM
Thrombin Ki = 35 nM
Trypsin Ki >2800 nM
Trypsin Ki >10000 nM
O
R2
S
F3C
F3C
R1
O
N
N
N
N
N
R3
O
O
NH2
NH2
O
O
N
Indoline Series
FXa Ki = 1.5 nM
N
Ketone Series
Table 1. Factor Xa and trypsin binding affinities, anticoagulation activity, and in vitro permeability for initial leadsa
F3C
R2
R1
SO2X
N
N
O
NH2
O
N
Compound
R1
R2
X
fXa Ki (nM)
Trypsin Ki (nM)
PT IC2x (lM)
aPTT IC2x (lM)
Caco-2 Papp (·10ꢀ6 cm/s)
1
H
H
H
F
CH3
NH2
CH3
NH2
CH3
NH2
CH3
NH2
0.68
0.53
0.07
0.16
4.7
>20,000
>20,000
>20,000
>20,000
>20,000
>20,000
>20,000
>20,000
—
18
9.0
12
—
—
—
112
—
33
9.3
18
—
—
—
30
—
2
H
bql
bql
31
3
H
4
H
F
5b
6b
7b
8b
CH3
CH3
CH3
CH3
H
H
F
—
—
22
2.8
—
bql
F
2.3
a Kis were obtained from purified human enzymes. Kis, PT, aPTT, and Caco-2 values were measured according to Ref. 4,8.
b Compounds are racemic.
to decrease binding affinity, in vitro clotting activity,
and surprisingly cellular permeability.
tively, than imidazole 9 and also had good activity in
the PT assay. The low Caco-2 data for pyrrolidine 11
are consistent with previous observations for this P4
group.4,9 Pyridone analogs 12 and 13 had very potent
fXa binding affinity, with pyridone 13 being significantly
more potent than its saturated counterpart. The relative
lack of activity in the PT assay for 12 and 13 compared
to 9–11, given their good binding affinity for fXa, sug-
gests that the pyridone analogs have greater protein
binding than their amine-containing P4 counterparts,
thus decreasing their antithrombotic efficacy in vitro.
Conversion of the carboxamido linker to a ketone in the
razaxaban scaffold initially afforded inhibitors with
subnanomolar binding affinity for fXa but low in vitro
anticoagulation activity and poor in vitro permeability.
To address these issues, P4 moieties that historically
have given good in vitro activity, attenuated protein
binding, and favorable pharmacokinetic profiles were
evaluated.4,8–10 All compounds of Table 2 had sub-
nano-molar binding affinities for fXa and high selectiv-
ity over trypsin. Imidazole 9 was 5-fold less active
toward fXa than razaxaban with 8-fold lower selectivity
over thrombin. However, 9 had significant activity in the
PT assay and comparatively high in vitro permeability
(razaxaban Caco-2 Papp = 5.6 · 10ꢀ6 cm/s). Benzylam-
ines 10 and 11 were 2- and 3-fold more potent, respec-
Compounds 9–11 met our in vitro criteria for fXa bind-
ing affinity and antithrombotic efficacy. As a result,
these P4 amines were tested in a dog pharmacokinetic
model and were found to have high clearance rates,
short half-lives, and poor bioavailability (Table 3). To
address these problems we revisited studies by our group

J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 749–754
751
Table 2. Factor Xa, thrombin, and trypsin binding affinities, clotting activity, and in vitro permeability for P4 modificationsa
F3C
R
N
N
P4
O
NH2
O
N
Compound
R
H
P4
fXa Ki (nM)
Thrombin Ki (nM)
Trypsin Ki (nM)
PT IC2x (lM)
Caco-2 Papp (·10ꢀ6 cm/s)
N
N
9
0.97
350
>4200
2.0
24
—
4
N
N
10
F
0.57
—
>4200
5.8
N
11
12
13
H
H
F
0.32
0.34
0.033
310
—
>4200
3.2
0.9 0.1
O
O
>20,000
>15,000
8.1
23
N
N
349
11.6
7.6
a Kis were obtained from purified human enzymes. Kis, PT, aPTT, and Caco-2 values were measured according to Ref. 4,8.
Table 3. Ketone pharmacokinetic profilesa
tion activity was also decreased for both PT and aPTT
assays in comparing 14–2. Fluorine incorporation im-
parted a modest 2-fold increase in binding for sulfon-
amide 15. Both hydroxypyrrolidine 16 and
tetrahydropyridone 17 were more active than 14 in both
binding (4-fold) and clotting assays (2-fold). As seen
previously with aminobenz-isoxazoles 12 and 13, pyri-
done 18 was 10-fold more active than 17. However, no
impact on PT efficacy was observed. To attenuate the
lipophilicity of what was perceived to be a highly pro-
tein-bound molecule, the 3-trifluoromethyl functionality
of the pyrazole of 18 was replaced with a C-linked pri-
mary amide.10 It was thought that this modification
would provide an increase in clotting activity due to re-
duced protein binding. Gratifyingly, the resulting 3-
amidopyrazole (19) improved potency in the PT and
aPTT assays by 3- and 6-fold, respectively.
Compound Caco-2 Papp Cl
(·10ꢀ6 cm/s)
Vdss
T1/2
F%
(L/h/kg) (L/Kg) (po) (po)
Razaxaban
9
5.56
1.1
2.5
2.0
2.3
3.4
4.5
11
5.3
1.6
—
84
16
24
—
4
10
11
bql
4.9
0.85 0.07
12
3.6
a Compounds were dosed in an N-in-1 format at 0.5 mg/kg iv and
0.2 mg/kg po (n = 1).4,8
indicating that oral absorption, in addition to clearance
rates and volumes of distribution, could be improved,
albeit at the cost of fXa binding affinity, by incorporat-
ing neutral P1 substituents.11 We employed this strategy
by replacing the P1-aminobenzisoxazole of the ketone
series with a neutral p-methoxyphenyl group.
Table 5 illustrates the high selectivity of pyridone 19 for
factor Xa over other human enzymes. Compared to
razaxaban, 19 is much more selective with respect to
thrombin and less selective over chymotrypsin.
The p-methoxyphenyl analogs are presented in Table 4.
As seen previously for this P1 substituent, these com-
pounds exhibited good selectivity over thrombin and
trypsin.10,11 The P4 ortho-phenyl sulfonamides 14 and
15were less active than their P1 aminobenzisoxazole
analogs (2 and 4) by 23- and 43-fold, respectively. This
is also consistent with data obtained by our group indi-
cating that the P1 p-methoxyphenyl functionality de-
creases fXa binding affinity relative to the P1
aminobenzisoxazole by P7-fold.9 In vitro anticoagula-
Pyridone 19 met our in vitro criteria for advancement
and was evaluated in a dog pharmacokinetic model (Ta-
ble 6). Bioavailability was high, and, despite a low vol-
ume of distribution, the half-life of compound 19 was
equivalent to that of razaxaban because of a very low
rate of clearance (0.09 L/h/Kg).

752
J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 749–754
Table 4. Binding affinities and in vitro activity for p-methoxyphenyl P1 analogsa
R1
N
R2
N
R3
O
OMe
Compound
R1
R2
H
R3
fXa Ki (nM)
Thrombin, Ki (nM)
Trypsin Ki (nM)
PT IC2x (lM)
aPTT IC2x(lM)
SO2NH2
SO2NH2
14
CF3
12
>21,000
>2500
40
65
15
16
CF3
CF3
F
6.9
3.3
>21,000
>6300
>6000
>4200
—
16
—
44
OH
N
H
O
O
O
17
18
19
CF3
H
F
F
1.0
>15,000
>15,000
>15,000
>15000
>15000
>15000
17
22
5.2
34
30
5.1
N
CF3
0.09
0.11
N
CONH2
N
a Kis were obtained from purified human enzymes. Kis, PT, aPTT, and Caco-2 values were measured according to Ref. 4,8.
chloride or pivaloyl mixed anhydride. Treatment with
the enolates of esters 23a,b, the preparation of which
is shown in Scheme 3, afforded the corresponding
beta-keto esters. Hydrolysis and decarboxylation under
acidic conditions generated ketones 24–25.
Table 5. Enzyme selectivity profile of pyridone 19
Human enzyme (Ki)
Razaxaban (lM)
Pyridone 19 (lM)
Factor Xa
Trypsin
0.00019
>10
0.00011
>15
>15
8.9
Thrombin
Plasma Kallikrein
APC
0.540
>2.3
>20
The chemistry used to prepare acids 20and 21 has previ-
ously been described.4,11 Acid 22 was prepared from
amide 26, which was generated from commercially
available 1-(4-methoxyphenyl)hydrazine hydrochloride
according to the procedures of Ref. 7. Dehydration upon
treatment withtrifluoroacetic anhydride and pyridine was
followed by oxidation to the acid to give 22 (Scheme 2).
>38
>15
>15
1.7
Factor IXa
Factor XIa
Chymotrypsin
Plasmin
>9
>12
>8.5
>15
>28
>43
tPa
>33
All Ki values were obtained according to Ref. 4.
Esters used in the generation of the ketone scaffolds in
Scheme 1 were prepared according to Scheme 3. Com-
mercially available toluene 27 was brominated under
radical conditions using 2,20-azobis(2-methylpropionit-
rile) (AIBN) and N-bromosuccinimide. Displacement
of the bromide with sodium cyanide, hydrolysis under
basic conditions, and methylation with trimethylsilyldia-
zomethane afforded ester 29a. Ester 29bwas similarly
prepared by methylating commercially available acetic
acid 28. Pyridone 30 and imidazole 314 were installed
using Ullmann conditions in average yield to give esters
33 and 34, respectively. Coupling of 29a,b with boronic
acid 32a– c4 under Suzuki conditions afforded the corre-
Table 6. Pharmacokinetic profile of p-methoxyphenyl P1 analogsa
Compound Caco-2 Papp Cl
(·10ꢀ6cm/s)
Vdss
(L/h/kg) (L/Kg) (po) (po)
T1/2
F%
Razaxaban
19
5.56
2.2
1.1
0.09
3.4
0.65
5.3
5.4
84
117
a Compounds were dosed in an N-in-1 format at 0.5 mg/kg iv and
0.2 mg/kg po (n = 1).4,8
The general strategy for preparing compounds from the
ketone series is shown in Scheme 1. Carboxylic acids 20–
22 were first converted to either the corresponding acid

J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 749–754
753
1
1
2
R
R
R
a, b, c
OH
N
N
2
N
N
R
O
P4
O
O
OMe
P1'
P '
1
24 R1 = CF3
P4
25 R1 = CN
P1' =
P1' =
23a R2 = H
23b R2 = F
CN
20 R1 = CF3
F
OMe
21 R1 = CF3
22 R1 = CN
Scheme 1. Reagents: (a) (COCl)2, DMF, CH2Cl2 or PivCl, Et3N, CH2Cl2; (b) ester 23a or 23b, nBuLi, DIA, THF, 65–88% (two steps); (c) 4 M
H2SO4/MeOH, 40–88%.
followed by synthesis of the lactam employing 5-bromo-
pentanoyl chloride and two equivalents of potassium
tert-butoxide. Conversion to the aminobenz-isoxazole
was carried out using acetohydroxamic acid and potas-
sium carbonate in low yield. The same chemistry was
employed when the P1 substituent was a p-methoxy-
phenyl group.
O
NC
H N
2
O
O
N
N
a, b
N
N
OH
OMe
26
OMe
22
Compounds containing methyl substituents alpha to the
ketone carbonyl (5–8) were prepared by converting acids
27 and 28 to the corresponding tert-butyl-dimethylsilyl
esters (TBSCl, Im, DMF, 55–80%). Coupling with acid
20 according to Scheme 1 was followed by methylation
with lithium hexamethyl-disilazide and excess iodometh-
ane. The biphenyl P4 group was then prepared via Suzu-
ki couplings with boronic acids 32a,b according to
Scheme 3 and conversion to the aminobenz-isoxazole
according to Scheme 4, albeit in greater yield (33–
80%). Sulfone and sulfonamide P4 moieties were gener-
ated from their corresponding thioanisole and tert-butyl
sulfonamide analogs upon treatement with meta-chlor-
operoxy-benzoic acid (CH2Cl2, 30–80%) and trifluoro-
acetic acid (6–90%), respectively.
Scheme 2. Reagents and condition: (a) TFAA, py, dioxane, 73%; (b)
KMnO4, tBuOH, 5% NaH2PO4, H2O, 60 ꢁC, 71%.
sponding biphenyl analogs 35a–c. Reductive amination
of benzaldehyde 35c with the appropriate amine gener-
ated the desired P4 benzyl amines.
Compounds containing tetrahydropyridone P4 groups
were prepared according to the procedure of Scheme
4. Ketone 36 was synthesized by coupling commercially
available ethyl 2-(4-nitrophenyl)acetate with acid 20
using the chemistry shown in Scheme 1. Reduction of
the nitro group with stannous chloride dihydrate was
F
e
N
F
HN
O
OMe
OMe
O
I
O
33
a, b, c, d
30
e
27
N
R1
I
N
H
N
O
O
N
OMe
34
29a R1 = F
29b R1 = H
N
d
31
f
R1
R2
I
O
R2
28
O
OH
OMe
B(OH)2
35a R2 = SCH3, R1 = H or F
35b R2 = SO2NHtBu, R1 = H or F
35c R2 = CHO, R1 = H or F
32a R2 = SCH3
32b R2 = SO2NHtBu
32c R2 = CHO
g
g
35d R2 = CH2-pyrrolidine, R1 = H
35e R2 = CH2N(CH3)2, R1 = F
Scheme 3. Reagents and conditions: (a) NBS, AIBN, acetone, reflux, 73% (b) NaCN, TBAB, tol/H2O, reflux, 54%; (c) NaOH, 2:1 EtOH/H2O, reflux,
96%; (d) TMSCH2N2, C6H6, MeOH, 66%; (e) 30 or 31, CuI, K2CO3, DMSO, 30–40%; (f) Pd2(dba)3, PPh3, Na2CO3, tol/H2O/EtOH, 33–90%; (g)
pyrrolidine or dimethylamine, NaBH(OAc)3, ClCH2CH2Cl, 50–72%.

754
J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 18 (2008) 749–754
3. (a) Walenga, J. M.; Jeske, W. P.; Hoppensteadt, D.;
F C
3
F C
3
O
Fareed, J. Curr. Opin. Invest. Drugs 2003, 4, 272; (b)
Samama, M. M. Thromb. Res. 2002, 106, v267; (c) Kaiser,
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Knabb, R. M.; Wong, P. C.; Wexler, R. R. J. Med. Chem.
2005, 48, 1729.
N
N
N
a, b, c
N
N
F
NO
O
2
O
NH
2
CN
O
N
12
36
Scheme 4. Reagents: (a) SnCl2Æ2H2O, EtOAc/EtOH, 86%; (b)
ClC(O)(CH2)4Br, KOtBu (2.0 equiv), THF, 45%; (c) CH3CONHOH,
K2CO3, DMF/H2O, 2%.
5. (a) Ioannides, C.; Lewis, D. F. V.; Trinick, J.; Neville, S.;
Sertkaya, N. N.; Kajbaf, M.; Gorrod, J. W. Carcinogen-
esis 1989, 10, 1403; (b) Chung, K.-T.; Chen, S.-C.; Li, T.
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Galemmo, R. A.; Amparo, E.; Wells, B.; Ellis, C.; He, M.
Y.; Alexander, R. S.; Rossi, K. A.; Smallwood, A.; Wong,
P. C.; Luettgen, J. M.; Rendina, A. R.; Knabb, R. M.;
Mersinger, L.; Bai, S.; He, K.; Kettner, C.; Wexler, R. R.;
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L.; Ellis, C. D.; Ming, Y. H.; Luettgen, J. M.; Knabb Bai,
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Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.;
Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.;
Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.;
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Pyridone 19 was prepared from the product of the cou-
pling of acid 22 and ester 33. Subsequent hydration
(H2O2, K2CO3, DMSO, 13%) of the nitrile substituent
of the pyrazole afforded the corresponding 3-amidopy-
razole 19 in low yield.
In conclusion, modification of the razaxaban pyrazole-
based scaffold by converting the carboxamido linker of
the pyrazole and proximal phenyl moieties to a ketone
has resulted in a new series of fXa inhibitors. Compounds
of this series consistently demonstrated high binding
affinity for factor Xa and good selectivity over thrombin
and trypsin. Good activity was obtained in clotting assays
with compounds containing protonatable nitrogens in the
P4 group, however, oral bioavailability in in vivo studies
remained low. Replacement of the P1-aminobenzisoxaz-
ole with a p-methoxyphenyl residue in order to improve
pharmacokinetic properties afforded compounds with
good fXa binding affinity but low activity in clotting as-
says. Subsequent conversion from a 3-trifluoromethyl to
a 3-amidopyrazole provided pyridone 19, a fXa inhibitor
with a fXa Ki of 0.11 nM and activity in PT and aPTT as-
says of approximately 5 lM. Pyridone 19had alow rate of
clearance, high oral bioavailability, a half-life equivalent
to that of razaxaban, was highly selective over a number
of human enzymes, and represents a successful optimiza-
tion of the 5-ketopyrazole scaffold.
9. Quan, M. L.; Han, Q.; Fevig, J.; Lam, P.; Bai, S.;
Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler, R.
R. Bioorg. Med. Chem. Lett. 2006, 16, 1795.
10. Pinto, D. J. P.; Orwat, M. J.; Koch, S.; Rossi, K. A.;
Alexander, R. S.; Smallwood, A.; Wong, P. C.; Rendina,
A.; Luettgen, J. M.; Knabb, R. M.; He, K.; Xin, B.;
Wexler, R. R.; Lam, P. Y. S. J. Med. Chem. 2007, 50,
5339.
11. Lam, P. Y. S.; Clark, C. G.; Li, R.; Pinto, D. J. P.; Orwat,
M. J.; Galemmo, R. A.; Fevig, J. M.; Teleha, C. A.;
Alexander, R. S.; Smallwood, A. M.; Rossi, K. A.;
Wright, M. R.; Bai, S. A.; He, K.; Luettgen, J. M.; Wong,
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References and notes
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