Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues

Article abstract of DOI:10.1016/j.bmcl.2006.11.071

The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a,

Full text of DOI:10.1016/j.bmcl.2006.11.071

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1432–1437
Pyrazole-based factor Xa inhibitors containing
N-arylpiperidinyl P4 residues
Jennifer X. Qiao,* Xuhong Cheng, Joanne M. Smallheer, Robert A. Galemmo,
Spencer Drummond, Donald J. P. Pinto, Daniel L. Cheney, Kan He, Pancras C. Wong,
Joseph M. Luettgen, Robert M. Knabb, Ruth R. Wexler and Patrick Y. S. Lam
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA
Received 8 November 2006; accepted 29 November 2006
Available online 1 December 2006
Abstract—The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing
substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog
16a, with a 20-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki = 0.35 nM)
based on potency, selectivity, and pharmacokinetic profile.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Thromboembolic diseases remain the leading cause of
death and disability in developed countries. Convention-
al antithrombotic therapies using either heparin or war-
farin have some limitations. In the past decade, several
approaches have been pursued to discover safer and
more efficacious oral anticoagulants. One promising
strategy is to inhibit thrombin generation by targeting
the inhibition of coagulation factor Xa (FXa). In the
coagulation cascade, FXa serves as the convergent point
of the intrinsic and extrinsic pathways. FXa binds
phospholipid, factor Va, and calcium ions to form the
prothrombinase complex. This complex converts pro-
thrombin to thrombin. Thrombin catalyzes the conver-
sion of fibrinogen to fibrin to form a clot. Studies in
animal models of thrombosis suggest that specific FXa
inhibitors might be more efficient, and have fewer bleed-
ing risks with a more favorable safety/efficacy ratio com-
pared to direct thrombin inhibitors.1,2
Recently, using structure-based approaches, the mono-
cyclic pyrazole SAR was extended to include potent
fused pyrazole FXa inhibitors such as 3.7
Both 1 and 2 contain an amide bond which could undergo
in vivo hydrolysis to release a biarylaniline fragment
which has the potential to be mutagenic.7 A non-aromatic
ring, such as 4-aminopiperidine, can be used in place of
the aniline moiety to remove this potential liability (see
Fig. 1, step one). Tying back the amide bonds in the result-
ing monocyclic pyrazoles led to a series of 7-oxo-4,5,6,7-
tetrahydro-1H-pyrazolo[3,4-c]pyridine bicyclics (fused
pyrazoles, Fig. 1, step two). In this paper, we present the
SAR and syntheses of both monocyclic and fused pyraz-
oles bearing substituted N-arylpiperidinyl moieties that
occupy the S4 binding pocket of FXa.
Monocyclic pyrazoles bearing N-arylpiperidinyl P4 moie-
ties. Structural modifications of 1 (DPC423), in which
the inner 2-fluorophenyl ring in 1 was replaced by an ali-
phatic ring, are shown in Table 1. Compounds 4–7 had
decreased FXa activity compared with 1, presumably
due to the changes in relative spatial orientation be-
tween the two substituents at the 1 and 4 positions of
the aliphatic rings. Cyclohexenyl, trans-cyclohexyl, and
piperidinyl analogs 4, 5, and 7 were all about 10 times
less potent against FXa than 1. In contrast, the cis-cy-
clohexyl isomer 6 was 300-fold less potent. The similar
FXa activity observed in the trans-cyclohexyl isomer 5
and piperidine 7 is most likely due to the resemblance
Previously, DPC423 (1) was reported as a highly potent
and orally bioavailable inhibitor of FXa from our labo-
ratories.3,4 Subsequently, Razaxaban (2), another pyra-
zole-based FXa inhibitor, with good potency,
selectivity, and efficacy in humans was disclosed.5,6
Keywords: Factor
N-Arylpiperidine.
Xa
inhibitors;
Pyrazole-based;
SAR;
*
Corresponding author. Tel.: +1 609 818 5298; fax: +1 609 818
6810; e-mail: jennifer.qiao@bms.com
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.071

J. X. Qiao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1432–1437
1433
N
F3C
F
HCl
F3C
F3C
F
N
N
H
N
H
N
N
SO2CH3
N
N
N
N
N
N
N
O
O
O
NH2
NH2
NH2
3 FXa Ki = 0.04 nM
O
N
O
N
1 (DPC423) FXa Ki = 0.3 nM
2 (Razaxaban) FXa Ki = 0.19 nM
F3C
F
H2NOC
F3C
R
H
N
SO2CH3
H
N
R
tying back amide bond
N
4-aminopiperidine
N
N
N
to form fused pyrazoles
as aniline isostere
N
N
N
P1
N
P1
N
O
O
O
step two
step one
P1
NH2
P4
P4
P4
16a-j
1 (DPC423) FXa Ki = 0.3 nM
4-11
Figure 1. Overall strategy.
Table 1. Structural modifications of 1 (DPC423)a,b
of the preferred bioactive conformations in these two
molecules: 1,4 di-equatorial substitution.
F3C
SO2Me
H
N
N
A
N
O
Among analogs bearing different P1 groups (com-
pounds 7, 8, 9a, and 11a in Table 1), the 3-aminoben-
zisoxazole analog 9a (FXa Ki = 1.7 nM) was the most
potent. Introduction of a piperidinone ring in 10 in
place of the piperidine ring resulted in a 50-fold de-
crease of FXa activity. Replacement of the 3-amino-
P
1
1, 4-11a
Compound P1
A
FXa Ki
(nM)
F
1
3-NH2CH2-Phenyl
3-NH2CH2-Phenyl
3-NH2CH2-Phenyl
3-NH2CH2-Phenyl
3-NH2CH2-Phenyl
2-NH2CH2-Phenyl
3-Aminobenzisoxazole-5-yl
3-Aminobenzisoxazole-5-yl
4-Methoxyphenyl
0.30
3.0
5.7
2000
4.9
2.4
1.7
92
benzisoxazole
p-methoxyphenyl P1 group in 11a led to a 10-fold
drop in FXa activity.
P1
group
with
the
neutral
4
A variety of N-substitutions on the piperidinyl ring of
analog 9a were then investigated. Table 2 shows the
in vitro data and pharmacokinetic profiles in dogs of
some representative compounds. N-phenyl piperidines
with an ortho substituent on the phenyl ring, such
as SO2Me or CH2NR1R2, provided the most potent
FXa inhibitors, following the same SAR trend previ-
ously observed with the biaryl P4 analogs.9 Benzyl-
amine analogs 9b–9e had FXa Ki less than 1 nM.
Compounds 9a–9e showed >1000-fold selectivity
against thrombin and were inactive against a panel
of serine proteases (trypsin, TPA, urokinase, activated
protein C, chymotrypsin, plasmin, and kallikrein).
Good anticoagulant activity in the human prothrom-
bin time (PT) assay6 was observed. However, these
monocyclic pyrazole analogs had undesirable pharma-
cokinetic profiles in dogs with high Cl and moderate
oral bioavailability (see Table 2). The negligible F%
in 9c and 9d is probably due to their low permeability
and/or the high first pass effect. Poor permeability was
consistent with the low Papp values observed in the
Caco-2 assay. In addition, compounds in Table 2
showed poor metabolic stability when incubated with
human liver microsomes (HLM). Despite its moderate
PK profile, compound 9b demonstrated a concentra-
tion-dependent antithrombolic effect with an EC50 val-
ue of 740 nM in the rabbit arterio-venous shunt
thrombosis model.10
5
6
7
N
N
N
8
9a
N
O
10
11a
14
N
a All compounds were purified by either reverse phase HPLC or pre-
parative LC/MS (water/acetonitrile gradient + 0.5% TFA). The basic
compounds were isolated as TFA salts following lyophilization. All
compounds gave satisfactory spectral and analytical data.
b Human purified enzymes were used. Values were averages from
multiple determinations (n > 2) and the standard deviations were
<30% of the mean. Ki values were measured as described in Ref. 8a.

1434
J. X. Qiao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1432–1437
Table 2. In vitro and dog PK profiles of monocyclic pyrazole analogs containing N-aryl piperidine P4 residues
F3C
R
H
N
N
N
N
O
NH2
9a-e
O
N
FXa Ki PT IC2x Caco-2 Papp · 10ꢀ6 HLM Clint
Cla
(mL/min/mg) (L/Kg/h) (L/Kg)a (h)
Vdss
po t1/2
F%b
b
Compound
R
(nM)
(lM)
(cm/s)
9a
9b
9c
9d
9e
–SO2Me
–CH2-N-Pyrrolidine
1.7
0.61
2.8
1.7
1.3
0.2
0.1
2.7
0.051
0.029
0.040
nd
1.1
2.9
2.2
6.4
4.3
2.6
13
1.3
5.0
24
26
0.84
0.83
1.2
c
c
–CH2-N-Pyrrolidine-2-(R)-OH 0.73
5.4
21.5
12.8
–CH2NHMe
–CH2NMeEt
0.67
0.70
0.3
2.5
1.7
23
1.1
0.029
nd, not determined.
a iv dose: 0.5 mg/kg.
b po dose: 0.2 mg/kg.
c BQL.
Scheme 1 illustrates a representative synthetic route for
the synthesis of the compounds in Table 2 using 9b as an
example. Arylation of 4-Boc-aminopiperidine with 2-flu-
orobenzaldehyde followed by reductive amination of 12
with pyrrolidine and NaBH(OAc)3 afforded amino
derivative 13. Coupling of 13 with acid 146 followed
by aminobenzisoxazole ring formation generated the de-
sired compound 9b. Compounds 9c–9e and 11a were
similarly prepared.
tuted piperidine P4 moieties. In order to balance the
polarity of these molecules, we selected a CONH2
group11 as the C-3 substituent on the pyrazole ring in-
stead of the more lipophilic CF3 group.
Table 3 shows the in vitro FXa activities of compounds
16a–j. In general, these fused pyrazole analogs were
more potent against FXa than their closely related
monocyclic derivatives. For instance, compound 16a
with
Ki = 0.35 nM) was 40 times more potent than the cor-
responding monocyclic compound 11a (FXa
a
20-methylsulfonylphenyl
group
(FXa
Fused pyrazoles bearing N-arylpiperidinyl P4 moieties.
Work by others11 in our laboratories with fused pyra-
zole analogs bearing biarylaniline P4 groups has demon-
strated that the neutral p-methoxyphenyl P1 group
might offer pharmacokinetic advantages. Further SAR
studies around the neutral p-methoxyphenyl P1 analog
11a with a variety of substituents on the piperidine ring
provided compounds with moderate potency (e.g., see
compounds 11b–d, Table 3). To improve the potency
of these neutral p-methoxyphenyl P1 analogs, the amide
NH was tied back to the C-4 of the pyrazole ring to gen-
erate a series of fused pyrazoles 16a–16j bearing substi-
Ki = 14 nM). Similarly, 16b bearing a N,N-dimethylm-
ethylamine R group (FXa Ki = 0.41 nM) was 20-fold
more active than its counterpart 11b (FXa
Ki = 8.8 nM). Among the wide variety of N-substituted
piperidinyl derivatives prepared, the most potent com-
pounds were those containing a substituted benzyl-
amine or a 20-methylsulfonylphenyl group. Other
than some micromolar thrombin activity, the fused
pyrazole analogs were selective over the other related
serine proteases noted previously. These compounds
NHBoc
F3C
NH2
N
NHBoc
F
OH
N
N
F
b,c
CHO
a
+
N
O
+
CHO
N
H
N
CN
12
14
13
F3C
F3C
N
N
H
N
H
N
N
N
e,f
d
N
N
N
N
F
O
O
9b
15
NH2
CN
O
N
Scheme 1. Reagents and condition: (a) K2CO3, DMSO, 85 ꢁC, 49%; (b) pyrrolidine, NaBH(OAc)3, ClCH2CH2Cl; (c) 4 N HCl/dioxane, then NaOH,
69% over 2 steps; (d) Castro’s reagent, NMM, DMF; (e) CH3CONHOH, K2CO3, DMF, H2O; (f) HPLC, 52% over 3 steps.

J. X. Qiao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1432–1437
1435
Table 3. SAR of fused pyrazole analogs 16a–16j bearing N-aryl piperidine P4 groups and comparison of factor Xa activities with the closely related
monocyclic pyrazoles 11a–11da,b
H2NOC
F3C
R
R
H
N
N
N
N
N
N
N
O
N
O
O
O
11a-d
16a-j
Compound 16a–j
R
FXa Ki (nM)
PT IC2x (lM)
Compound 11a–d
FXa Ki (nM)
16a
16b
16c
16d
16e
16f
16g
16h
16i
SO2Me
CH2N(Me)2
0.35
0.41
0.26
0.57
0.87
1.0
4.2
1.0
1.2
3.5
2.5
1.8
1.5
nd
11a
11b
11c
11d
14
8.8
29
CH2-N-Pyrrolidine
CH2-N-Morpholine
6.6
CH2-N-Pyrrolidine-2-(S)-OH
CH2NHMe
CH2NEt2
0.26
23
81
CH2N(Me)COMe
CH2N(Me)SO2Me
SO2NH2
nd
nd
16j
3.9
a
All compounds were purified by either reverse phase HPLC or preparative LC/MS (water/acetonitrile gradient + 0.5% TFA). The basic compounds
were isolated as TFA salts following lyophilization. All compounds gave satisfactory spectral and analytical data.
b
Human purified enzymes were used. Values were averages from multiple determinations (n > 2) and the standard deviations were <30% of the
mean. Ki values were measured as described in Ref. 8a. PT values are measured according to Ref. 6a.
also showed good anticoagulant activity in human
plasma in the clotting time assay (PT IC2x < 5 lM).
Sulfonamide 16j was 10-fold less potent than the corre-
sponding methylsulfone 16a. N-Acetyl analog 16h and
N-methylsulfonyl analog 16i were 20- and 40-fold less
potent, respectively, relative to the parent basic amine
compound 16f.
Scheme 2 exemplifies the synthesis of fused pyrazole
analogs bearing substituted N-arylpiperidine P4 groups
EtOOC
O
Cl
EtOOC
N
N
NH2
N
N
N
NH
O
N
Bn
a,b
N
c,d
e
f
O
O
N
+
N
N
Bn
N
O
OMe
Bn
N
Bn
O
17
21
18
20
19
EtOOC
H2NOC
H2NOC
EtOOC
MeO2S
MeO2S
N
N
N
N
h,i,j
N
g
N
N
N
NH
N
O
N
N
Bn
N
N
O
N
O
+
N
O
O
O
O
O
22
23
16a
24
O
j
16a : 24 = 1 : 1
O
H
N
N
H2NOC
H2NOC
H2NOC
N
N
N
N
N
N
N
m
k,l
N
NH
N
O
N
N
O
O
O
O
25
16f
16h
O
Scheme 2. Reagents and conditions: (a) Br(CH2)4COCl, aq K2CO3 (20% w/w), EtOAc, rt, 1 h; (b) KO-t-Bu, THF, 0 ꢁC, 0.5 h; 99% for 2 steps; (c)
PCl5, CHCl3, reflux, 3 h, 85%; (d) morpholine, reflux, overnight, 86%; (e) Et3N, toluene, 85 ꢁC, overnight; (f) 4 N HCl, CH2Cl2, rt, 4 h, 41% for 2
steps; (g) H2, Pd/C (10%), HOAc, MeOH, rt, 3 h, 94%; (h) o-SMe–PhB(OH)2 (2 equiv), Et3N (2 equiv), Cu(OAc)2 (1.5 equiv), 4 A freshly activated
˚
molecular sieves, rt, 72 h, 50%; (i) m-CPBA, CH2Cl2, rt; (j) NH3 in ethylene glycol, 85 ꢁC, 2 h, 53% for h–j; (k) o-F–Ph–CHO, K2CO3, DMSO, 85 ꢁC,
16 h, 78%; (l) NH2Me, NaBH(OAc)3, MeOH/CH2Cl2 (3:1), HOAc, rt, 2 h, 86%; (m) ClCOCH3, pyridine, CH2Cl2, rt, 2 h, 50%.

1436
J. X. Qiao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1432–1437
using compounds 16a, 16f, and 16h as examples. Start-
ing from commercially available 4-amino-1-benzylpi-
peridine 17, 1-(1-benzylpiperidin-4-yl)-piperidin-2-one
18 was formed in quantitative yield in two steps by con-
densation of 17 with 5-bromovaleryl chloride in the
presence of aqueous potassium carbonate, followed by
intramolecular displacement of the resulting bromide
in the presence of potassium tert-butoxide. Treatment
of 18 with three equivalents of phosphorus pentachlo-
ride followed by heating the resulting a,a-dichloropipe-
ridinone intermediate in morpholine afforded the
morpholino-enamine 19 in good yield at reflux. Conden-
sation of 19 with the chlorohydrazone 2011 in the pres-
ence of two equivalents of triethylamine in hot toluene
provided the morpholino intermediate 21, which was
then aromatized with 4 N HCl in methylene chloride
to afford the desired bicyclic 7-oxo-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridine skeleton 22 in moderate
yield. Removal of the benzyl group of 22 provided the
key intermediate 23. Intermediate 23 was treated with
2-(methylthio)phenylboronic acid, copper(II) acetate,
and triethylamine in the presence of freshly activated
molecular sieves under air, followed by oxidation with
meta-chloroperbenzoic acid, and then C3 primary amide
formation by heating in ethylene glycol saturated with
ammonia to give a mixture of 16a and its corresponding
N-oxide 24. Pure 16a was obtained after reverse phase
HPLC separation. Alternately, treatment of 23 with
ammonia in ethylene glycol provided amide 25 which
underwent SNAr arylation with 2-fluorobenzaldehyde.
Reductive amination with methylamine and sodium tri-
acetoxyborohydride afforded amino derivative 16f.
Treatment of 16f with acetyl chloride and pyridine pro-
vided the amide derivative 16h.
C191
C220
S4
S1
D189
S195
Figure 3. Overlay of proposed binding modes of 11a and 16a with
crystal structure of 1 (DPC423) in factor Xa.
Quantum mechanical calculations and analysis of small
molecule crystallographic data suggested that (1) the
amide carbonyl, which forms a hydrogen bond with
G216 NH, adopts a favored syn relationship with the
adjacent piperidinyl tertiary CH (Fig. 2); and (2) the
nitrogen atom of the N-arylpiperidine P4 group likely
adopts a tetrahedral (sp3) geometry, such that the pipe-
ridinyl C2 and C6 methylene groups are directed away
from the bulky ortho-methylsulfonyl substituent of the
phenyl ring.
Table 4 shows a comparison of the in vitro properties
and PK profile of fused pyrazole analog 16a and com-
pound 1 (DPC423). Both had similar FXa inhibitory
activity in the primary binding assay and similar poten-
cy in the functional clotting time assay. Compound 16a
had an improved selectivity profile compared with 1
with respect to trypsin and plasma kallikrein. Despite
The bioactive conformation of both fused pyrazole 16a
(Fig. 2) and monocyclic pyrazole 11a (Fig. 3) was as-
signed on the basis of crystal structures of related FXa
inhibitors bearing biaryl P4 moieties, for example, 1
(DPC423),3 quantum mechanical calculations,12 and
small molecule crystallographic data.13 Short MD simu-
lations14 suggested no significant differences in the over-
all binding motifs of 11a-FXa and 16a-FXa relative to 1.
Table 4. Comparison of in vitro and pharmacokinetic profiles (in
dogs) of pyrazoles 1 (DPC423) and 16a
In vitro and PK profiles
1 (DPC423)
16a
Factor Xa Ki (nM)
PT IC2x (lM)
0.30
3.5
0.35
4.2
F174
Thrombin Ki (nM)
Trypsin Ki (nM)
Plasma kallikrein (lM)
Activated protein C (lM)
Chymotrypsin (lM)
Urokinase (lM)
Plasmin (lM)
6000
60
1200
E146
>20,000
>11,000
>37,600
4475
61
1800
>17,000
>19,000
>35,000
>45,000
4.8
C191
C220
“H”
S4
>13,000
>28,000
>43,000
1.5
G216
W215
S1
tPA (lM)
Caco-2 Papp · 10ꢀ6 (cm/s)
HLM t1/2 (min)
Y99
124
117
D189
Cla (L/Kg/h)
Vdss (L/Kg)
b
po t1/2 (h)
F%b
0.24c
0.99c
7.5c
0.23d
0.33d
0.8d
S195
H57
57c
78d
a iv dose: 0.5 mg/kg.
Y228
Figure 2. Proposed binding mode of 16a in factor Xa.
b po dose: 0.2 mg/kg.
c From discrete dog PK study.
d From cassette dosing in dog PK studies.

J. X. Qiao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1432–1437
1437
4. Pruitt, J. R.; Pinto, D. J. P.; Galemmo, R. A., Jr.;
Alexander, R. S.; Rossi, K. A.; Wells, B. L.; Drummond,
S.; Bostrom, L. L.; Burdick, D.; Bruckner, R.; Chen, H.;
Smallwood, A.; Wong, P. C.; Wright, M. R.; Bai, S.;
Luettgen, J. M.; Knabb, R. M.; Lam, P. Y. S.; Wexler, R.
R. J. Med. Chem. 2003, 46, 5298.
5. 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, P. C.; Knabb, R. M.;
Wexler, R. R. J. Med. Chem. 2003, 46, 4405.
a relatively low Caco-2 Papp value, 16a showed good
oral bioavailability in dogs with F% = 78%. In fact,
16a showed low systematic clearance and good oral bio-
availability in dogs similar to 1 (DPC423). However, 16a
had a shorter t1/2 which may be due to its lower Vdss
.
Studies of possible metabolites of 16a, and search for
structural modifications to block or reduce the metabol-
ic pathways may improve the pharmacokinetic profile of
this series of compounds.
6. (a) Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.;
He, M. Y.; Li, R.; Ellis, C. D.; Clark, C. G.; Teleha, C. A.;
Sun, J.-H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.;
Knabb, R. M.; Wong, P. C.; Wexler, R. R. J. Med. Chem.
2005, 48, 1729; (b) Lessen, M. R.; Davidson, B. L.; Gallus,
A.; Pineo, G.; Ansell, J.; Deitchman, D. Blood 2003, 102,
15a, Abstract 41.
7. (a) Fevig, J. M.; Cacciola, J.; Buriak, J., Jr.; Rossi, K. A.;
Knabb, R. M.; Luettgen, J. M.; Wong, P. C.; Bai, S.;
Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett.
2006, 16, 3755; (b) Pinto, D. J. P.; Orwat, M. J.; Quan, M.
L.; Han, Q.; Galemmo, R. A.; Amparo, E.; Wells, B.;
Ellis, C.; He, M. Y.; Alexander, R. S.; Rossi, K. A.;
Smallwood, A. M.; Wong, P. C.; Luettgen, J. M.;
Rendina, A. R.; Knabb, R. M.; Mersinger, L.; Kettner,
C.; Bai, S.; He, K.; Wexler, R. R.; Lam, P. Y. S. Bioorg.
Med. Chem. Lett. 2006, 16, 4141.
In summary, a series of pyrazole analogs bearing substi-
tuted piperidine P4 groups were synthesized and identi-
fied as potent and selective FXa inhibitors in both
monocyclic pyrazole and bicyclic pyrazolopyridine
series. The fused pyrazole analogs containing a neutral
p-methoxyphenyl P1 group showed improved FXa
inhibitory activity relative to their monocyclic counter-
parts. Compound 16a, bearing a 20-methylsulfonylphe-
nyl piperidinyl P4 group, was one of the most potent
and selective compounds prepared in this series, offering
a PK profile with low Cl and good bioavailability simi-
lar to 1 (DPC423), but a shorter t1/2
.
References and notes
8. (a) Quan, M. L.; Liauw, A. Y.; Ellis, C. D.; Pruitt, J. R.;
Bostrom, L. L.; Carini, D. J.; Huang, P. P.; Harrison, K.;
Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R.
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12. (a) Conformational analysis was done using similar
protocols for N-cyclohexylacetamide and N-(2-meth-
ylsulfonyl)phenyl piperidine as model systems. Conforma-
tional ensembles of each model system were manually
generated in MacroModel (MMFFs force-field/GBSA
solvent model), and passed onto Jaguar for estimates of
relative conformational energies at LMP2/cc-pvtz(-f)++//
B3LYP/6-31G*; (b) MacroModel 9.0, Jaguar 6.0 Schro-
dinger, Inc., NY.
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203.
¨
13. Analysis of small molecular crystal data relating to the
substructures of interest was done using Conquest 1.7,
Cambridge Crystallographic Database, www.ccdc.cam.
ac.uk.
3. Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.;
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.;
Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. J. Med. Chem.
2001, 44, 566.
14. MD simulations were conducted with Discover_3 using
over
CFF98 force-field
www.accelrys.com.
24 ps
gas
phase.