Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure-activity studies leading to the discovery of RWJ-53308

Article abstract of DOI:10.1021/jm990418b

Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042 (racemate of 1), which was derived from a unique approach involving the γ-chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue studies culminated in the discovery of RWJ-53308 (2), a potent, orally active GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for clinical development, we conducted a series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and inhibition of platelet aggregation induced by four different activators. This strategy produced several promising analogues for advanced study, including 3-(3,4- methylenedioxybenzene)-β-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-β-amino acid 2 (significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical data, RWJ-53308 (2) was selected for clinical evaluation.

Full text of DOI:10.1021/jm990418b

5254
J . Med. Chem. 1999, 42, 5254-5265
P oten t, Or a lly Active GP IIb/IIIa An ta gon ists Con ta in in g a Nip ecotic Acid
Su bu n it. Str u ctu r e-Activity Stu d ies Lea d in g to th e Discover y of RWJ -53308
William J . Hoekstra,*,† Bruce E. Maryanoff,† Bruce P. Damiano,† Patricia Andrade-Gordon,† J udith H. Cohen,‡
Michael J . Costanzo,† Barbara J . Haertlein,† Leonard R. Hecker,† Becky L. Hulshizer,† J ack A. Kauffman,†
Patricia Keane,† David F. McComsey,† J ohn A. Mitchell,† Lorraine Scott,‡ Rekha D. Shah,‡ and
Stephen C. Yabut†
Drug Discovery and New Product Research, The R. W. J ohnson Pharmaceutical Research Institute,
Spring House, Pennsylvania 19477
Received August 17, 1999
Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists
have become established in the acute-care clinical setting for the prevention of thrombosis,
orally administered drugs for chronic use are still under development. Herein, we present details
from our exploration of structure-activity surrounding the prototype fibrinogen receptor
antagonist RWJ -50042 (racemate of 1), which was derived from a unique approach involving
the γ-chain of fibrinogen (Hoekstra et al. J . Med. Chem. 1995, 38, 1582). Our analogue studies
culminated in the discovery of RWJ -53308 (2), a potent, orally active GPIIb/IIIa antagonist.
To progress from RWJ -50042 to a suitable candidate for clinical development, we conducted a
series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient
preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and
inhibition of platelet aggregation induced by four different activators. This strategy produced
several promising analogues for advanced study, including 3-(3,4-methylenedioxybenzene)-â-
amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-â-amino acid 2
(significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed
significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral
bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally,
2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV)
shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and
guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy
preclinical data, RWJ -53308 (2) was selected for clinical evaluation.
In tr od u ction
to have drugs for oral administration in a chronic
regimen. Many fibrinogen receptor antagonists have
been designed on the basis of the integrin tripeptide
recognition motif Arg-Gly-Asp (RGD), which is present
in the AR-chain of fibrinogen. Since this has entailed
nonpeptide molecular scaffolds bearing basic and acidic
moieties to represent the Arg and Asp side chains,
respectively, the resulting zwitterionic species have not
been especially noted for oral bioavailability. This
problem has led researchers to a focus on prodrug
entities, such as xemilofiban6 and sibrafiban,7 which
have reached advanced stages of clinical development.
The serious cardiovascular disorders of myocardial
infarction and unstable angina are associated with the
activation and subsequent aggregation of platelets.
Adhesion of platelets to damaged blood vessel walls, or
following rupture of atherosclerotic plaque, triggers a
constellation of events that promote thrombus formation
and arterial thrombosis. The final step in platelet
aggregation, which is common to diverse activating
agents such as ADP, collagen, and serotonin, involves
the adhesive protein fibrinogen.1 This large molecule
binds to the activated, membrane-bound glycoprotein
(GP) IIb/IIIa complex to cross-link platelets as part of
a growing thrombus. Because of the central role played
by this integrin, compounds that compete effectively
with fibrinogen at its receptor can serve as potent
antithrombotic agents.2 Indeed, the prevention of throm-
bosis by such “fibrinogen receptor antagonists” has been
clinically established and three intravenous drugs have
reached the marketplace: the monoclonal antibody
abciximab,3 the cyclic peptide eptifibatide,4 and the
nonpeptide tirofiban.5 Although these drugs are effica-
cious in an acute-care setting, it would also be desirable
Because the RGD sequence is present in a variety of
adhesive proteins, we originally set out on an alternative
approach involving the KQAGD sequence in the γ-chain
of fibrinogen, which is known to be important in the
binding of fibrinogen to GPIIb/IIIa.8 By means of NMR
studies on the C-terminal γ-chain peptide from positions
385-411, we ascertained the presence of a turn geom-
etry in the key KQAGD domain (γ406-410).9-13 We
* Corresponding author. Fax: 215-628-4985. E-mail: whoekstr@
prius.jnj.com.
† Drug Discovery.
‡ New Product Research.
10.1021/jm990418b CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/13/1999

Discovery of RWJ -53308
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5255
Sch em e 2. Synthesis of 3-Ethynyl-â-amino Estersa
Sch em e 1. Synthesis of 2a
a
(a) R-CC-Li, THF, -78 °C. (b) 4 N HCl/1,4-dioxane/MeOH. (c)
(R)-PhCH(OMe)COCl, NMM. (d) Silical gel chromatography. (e)
Boc2O, DMAP. (f) N,N,N′,N′-Tetramethylguanidine, MeOH. (g) 4
N HCl/1,4-dioxane.
a
(a) Malonic acid, NH4OAc, EtOH, reflux. (b) PhCH2COCl,
Sch em e 3. Ephedrine Salt Resolution of a â-Amino
Et3N, aq acetone. (c) Penicillin amidase, pH 7.5. (d) 6 N HCl (aq).
(e) 4 N HCl/1,4-dioxane/MeOH. (f) N-Boc-(R)-nipecotic acid, HBTU,
HOBT, NMM, MeCN. (i) LiOH, aq THF. (j) 4 N HCl/1,4-dioxane.
Acida
then used nipecotic acid as a scaffold and appended the
appropriate Lys and Asp moieties to arrive at a novel
series of compounds, represented by 1 (R-isomer of
RWJ -50042).14 Although nipecotamide 1 exhibited oral
activity, it had modest potency and a short duration of
action in vivo (ex vivo inhibition of platelet aggregation
following oral administration to dogs at 10 mg/kg). A
well-focused optimization program that relied heavily
on the rapid, solid-phase parallel synthesis of ana-
logues15 solved this problem quickly and delivered a
potent clinical candidate, RWJ -53308 (2). Significantly,
a
Malonic acid, NH4OAc, EtOH, reflux. (b) BOC2-O, Et3N, aq
1,4-dioxane. (c) (1R,2S)-ephedrine, EtOAc, crystallization. (d) 10%
citric acid/CHCl3. (e) 4 N HCl/1,4-dioxane/MeOH.
Analogues of 3 were synthesized from resolved â-ami-
no esters (e.g., 6) by the general route shown for
pyridine 2 in Scheme 1. The secondary amide was
formed by HBTU (2-[1H-benzotriazol-1-yl]-1,1,3,3-tet-
ramethyluronium hexafluorophosphate) activation of
N-Boc-(R)-nipecotic acid and addition of â-amino ester
6 at 5 °C; Boc removal with hydrochloric acid then gave
secondary amine 7. The tertiary amide was formed by
coupling with HBTU-activated N-Boc-4-piperidinepro-
panoic acid and purified by flash column chromatogra-
phy. Typically, the HBTU couplings were effected in
65-95% yields. The purified ester was saponified with
lithium hydroxide and the Boc group was removed with
hydrochloric acid to give the product for in vivo study.
Since the literature is replete with enantioselective
syntheses of â-amino acids, suitable methods for any
particular resolved â-amino ester (e.g., 6) are available.
Generally, we used a modified Knoevenagel condensa-
tion18 of aldehyde 4 with malonic acid/ammonia to afford
the racemic â-amino acid, then separated enantiomers
by classical resolution of diastereomeric salts. Alterna-
tively, asymmetric synthesis could be employed. For
instance, the synthesis of the 3-(3,4-methylenedioxy-
benzene)-â-amino ester for 3 was accomplished in high
diastereomeric excess by using an asymmetric Michael
addition of lithiated R-methylbenzylamine to the req-
uisite cinnamate.15,19 For pyridyl-containing 6, however,
removal of the R-methylbenzyl chiral auxiliary group
resulted in poor yields. A better method here was
resolution of phenylacetamide 5 with penicillin amidase
(Scheme 1).20 3-Ethynyl-â-amino esters (11) were pre-
pared from 4-acetoxyazetidinone (8) as reported (Scheme
2).6b For large-scale preparation of resolved esters,
ephedrine salt resolution of the N-Boc-â-amino acid (13)
was employed, as exemplified in Scheme 3.6b For the
preparation of antagonists 37-39, the resolved tert-
butyl â-amino esters were purchased from Oxford
Asymmetry (Table 1).
this compound can be dosed both intravenously and
orally, has a good duration of action, and demonstrates
excellent safety characteristics. Herein, we report de-
tails of the optimization process, solid-phase synthesis,
structure-activity relationships, and enantioselective
scale-up synthesis connected with our novel nipecota-
mide class of fibrinogen receptor antagonists.
Resu lts a n d Discu ssion
Syn th esis of An a logu es of RWJ -50042. Given the
competitive environment surrounding the GPIIb/IIIa
area of antithrombotic therapy,2 we had pursued syn-
thetic methodology to expedite the rapid preparation of
analogues of 1: namely, solid-supported parallel organic
synthesis.16,17 In our preliminary report, we used a
synthetic procedure involving N-terminal attachment
of the substrate to a 2-chlorotrityl resin and found that
substitution on the â-amino acid carbon of 1 with an
arene is important for potency improvement.15 Com-
pound 3 represented early success from the parallel
synthesis arrays and sufficient quantities were then
obtained by enantioselective synthesis.

5256 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Hoekstra et al.
Ta ble 1. Biological Data for Variant â-Amino Acid GPIIb/IIIa Antagonists
human GFPa
IC50 (µM)
Fg bindingb
IC50 (nM)
oral duration,c
min (3 mg/kg)
compd
R1
R2
R3
R4
1
2
3
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
0.27 ( 0.08
0.06 ( 0.01
0.02 ( 0.01
0.84 ( 0.67
36 ( 4
4.8 ( 2.0
0.36 ( 0.27
0.50 ( 0.20
0.24 ( 0.14
48 ( 28
120
360
180
120d
<30
NDe
<30f
ND
ND
150f
ND
ND
ND
ND
ND
ND
ND
30
(S)-3-pyridyl
(S)-3,4-methylenedioxy-Ph
(S)-3,4-methylenedioxy-Ph
(S)-3,4-methylenedioxy-Ph
(R)-CtCPh
(S)-CtCPh
(R)-CtC-t-Bu
27
28
29
30
31
32
33
34g
35
36
37
38h
39
40
41
3.5 ( 0.5
0.29 ( 0.06
0.22 ( 0.13
5.6 ( 1.7
0.08 ( 0.08
31 ( 18
(S)-CtC-t-Bu
0.08 ( 0.02
0.02 ( 0.03
1.2 ( 0.40
0.09 ( 0.02
0.04 ( 0.00
8.0
42 ( 10
(S)-3-quinolinyl
(S)-3-quinolinyl
(S)-2-thienyl
(S)-5-Cl-2-thienyl
(R)-Me
(R)-CH2Ph
(R)-CH2Ph
H
0.18 ( 0.05
0.37 ( 0.11
0.10 ( 0.03
0.10 ( 0.03
13.5 ( 8.5
0.37 ( 0.24
17.9 ( 5.1
3.5 ( 1.5
0.97 ( 0.33
0.21 ( 0.01
1.6 ( 0.35
11.8 ( 2.7
0.30 ( 0.10
(S)-OH
(R,S)-OH
H
(S)-3-Cl-5-CF3-2-pyridyl
66.8 ( 7.5
2.0 ( 1.0
Xemilofiban
(SC-54684)
>180
a
b
Thrombin-induced gel-filtered platelet aggregation (n ) 2). Inhibition of biotinylated fibrinogen binding to immobilized GPIIb/IIIa
(n ) 2). c Oral duration of at least 50% inhibition of collagen-induced platelet aggregation (ex vivo). 10 mg/kg oral dose. e No data. f 1
mg/kg oral dose. (S)-Nipecotic acid. Racemic nipecotic acid.
d
g
h
Ta ble 2. GPIIb/IIIa Binding Data for 5-Substituted Pyridines
Isolated Following Resin-Bound Suzuki Couplings
Sch em e 4. Solid-Phase Synthesis of 5-Substituted
Pyridines by Suzuki Cross-Couplinga
Fg bindingb
IC50 (nM)
FAB-MS
compda
R
m/e (MH+) yield (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Br
3.0 ( 0.6
2.0 ( 0.0
36 ( 4
495,497
499
533
533
508
523
523
543
543
523
538
493
507
499
417
36
41
50
52
99
49
53
50
52
49
43
17
39
40
55
3-thienyl
2-benzofuranyl
5-Cl-2-thienyl
3-NH2-Ph
3-OMe-Ph
4-OMe-Ph
1-naphthyl
2-naphthyl
2-OMe-Ph
3-NO2-Ph
Ph
57 ( 41
3.6 ( 0.5
11 ( 5.6
11 ( 4.7
26 ( 13
57 ( 38
12 ( 1.8
14 ( 7.9
1.8 ( 0.0
24 ( 1.5
1.5 ( 0.1
3.0 ( 0.0
a
(a) ArB(OH)2, (Ph3P)4Pd, Na2CO3, DME. (b) KOTMS, THF.
(c) TFA, CH2Cl2.
To elaborate further the structure-activity relation-
ships around the pyridine ring of 2, N-terminal 2-chlo-
rotrityl resin attachment of 5-bromopyridine 15 pro-
vided a key Suzuki cross-coupling intermediate (Scheme
4). Boronic acids were cross-coupled with 15 using
methodology reported by Ellman in good purity (>90%,
Table 2).21 Construction of 15 starting from the 2-chlo-
rotrityl chloride resin and allyl 3-(4-piperidine)pro-
panoate was carried out as reported.15,22 Intermediate
Suzuki cross-coupling products 16 were then saponified
on the resin with potassium trimethylsilanolate in THF
and cleaved from the resin with trifluoroacetic acid
(TFA) to afford 42b-n . Solution-phase Suzuki meth-
odology was employed to prepare thiophene 46 from a
6-chloropyridine precursor (Table 3).23 Enantioselective
4-Me-Ph
2-thienyl
H
a
Compounds are racemic with respect to both stereogenic
b
centers. Inhibition of biotinylated fibrinogen binding to im-
mobilized GPIIb/IIIa (n ) 2).
follow-up syntheses of desirable 5-substituted pyridine
intermediates 19a -c were accomplished starting from
5-bromonicotinate 17 (Scheme 5). Palladium(0)-medi-
ated alkyne coupling followed by lithium aluminum

Discovery of RWJ -53308
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5257
Ta ble 3. Biological Data for Resolved Pyridyl GPIIb/IIIa Antagonists
human GFPa
IC50 (µM)
Fg bindingb
IC50 (nM)
oral duration,c
min (3 mg/kg)
compd
R1
R2
43
44
45
46
47
48
49
50
51
52
H
Br
H
Me
H
Cl
0.03 ( 0.01
0.02 ( 0.00
0.02 ( 0.00
0.20 ( 0.05
0.22 ( 0.08
0.090
0.07 ( 0.01
0.04 ( 0.00
0.03 ( 0.00
0.03 ( 0.00
0.13 ( 0.04
0.21 ( 0.07
0.14 ( 0.01
0.37 ( 0.07
0.34 ( 0.11
3.8 ( 2.9
0.52 ( 0.02
0.85 ( 0.05
0.66 ( 0.22
0.24 ( 0.06
210
180
210
150
150
30
ND
<30d
180
ND
H
3-thienyl
Cl
Cl
Ph
Cl
OMe
H
H
H
PhCtC
PhCH2CH2
HCtC
H
a
b
Thrombin-induced gel-filtered platelet aggregation (n ) 2). Inhibition of biotinylated fibrinogen binding to immobilized GPIIb/IIIa
(n ) 2). c Oral duration of at least 50% inhibition of ADP-induced platelet aggregation (ex vivo). 1 mg/kg oral dose.
d
Sch em e 5. Synthesis of Resolved 3-(5-Alkynyl-3-
pyridyl)-â-amino Estersa
realized with bulky, S-configured â-aryl and â-het-
eroaryl groups such as 3,4-methylenedioxybenzene (3;
IC50 ) 20 nM), 3-quinoline (33; IC50 ) 20 nM), and
5-chloro-2-thiophene (36; IC50 ) 40 nM). Consistent with
these results, 3, 33, and 36 showed remarkable receptor
affinities (IC50 values of 0.50, 0.18, and 0.10 nM,
respectively). The 3-pyridyl (2) and 2-thienyl (35) ana-
logues also showed very respectable potency in platelet
aggregation (IC50 values of 60 and 90 nM, respectively).
The 2-alkynyl analogues (30, 32) were quite potent
against platelet aggregation (IC50 values of 80 nM),
although 32 showed less potency in GPIIb/IIIa binding
(IC50 ) 42 nM).
a
(a) Ph-CC-H or TMS-CC-H, (Ph3P)2PdCl2, Et3N, CuI, EtOAc.
(b) LiAlH4, THF. (c) PDC, CH2Cl2. (d) Malonic acid, NH4OAc,
EtOH, reflux. (e) Boc2O, Et3N, aq 1,4-dioxanel. (f) (1R,2R)-
Ephedrine, EtOAc, crystallization. (g) 10% citric acid/CHCl3. (h)
4 N HCl/1,4-dioxane/MeOH. (i) K2CO3, EtOH. (j) H2, 10% Pd-C,
MeOH.
The pharmacology of selected antagonists was studied
in canine ex vivo platelet aggregation inhibition experi-
ments (Table 1). Dogs (n ) 3) were orally administered
an aqueous solution of 3 mg/kg compound, and blood
samples were drawn at 30-min intervals. The blood
sample was treated with ADP (20 µM) to measure
platelet aggregation. To assess the pharmacokinetics of
the antagonists, dogs were dosed intravenously as well,
at one-third or one-tenth of the oral dose (data shown
for 2). While the 3,4-methylenedioxybenzene analogue
3 produced at least 50% inhibition for a 180-min
duration, its more hydrophobic N-methylpiperidine (27)
and ethyl ester (28) analogues each inhibited aggrega-
tion at least 50% for only 120 min. Similarly, quinoline
33 exhibited a duration of action of 150 min. A phar-
macokinetics study of 3 in dogs revealed an oral
systemic availability of 14 ( 2% (AUC method), with
intravenous and oral plasma half-lives of 21 ( 2 min
and 108 ( 36 min, respectively (based on plasma levels
of 3). While 3 possessed adequate in vivo potency, its
overall pharmacodynamic profile was too deficient to be
considered for preclinical development.
hydride reduction to the alcohol and oxidation of the
alcohol gave the pyridine-3-carboxaldehydes 18. Modi-
fied Knoevenagel condensation,18 N-Boc protection,
ephedrine salt resolution by crystallization, and protect-
ing group manipulation afforded 19a -c for use in
syntheses exemplified by Scheme 1. Amidine 54 was
prepared by acylation of secondary amine 53 with ethyl
formimidate hydrochloride (Table 4).24 For alkene 56,
intermediate N-Boc-3-(4-piperidine)prop-2-enoic acid
(21) was prepared by Wittig reaction of ethyl 2-(triph-
enylphosphoranylidene)acetate with the aldehyde de-
rivative of 20 (Scheme 6). Tris-protected piperazine
scaffold 24 was prepared as a precursor to 57 starting
from 2,3-diaminopropionate 22, as reported (Scheme
7).25 Racemic methyl pyrrolidine-3-carboxylate (26) was
prepared in two steps from commercially available
lactam 25 for target 58 (Scheme 8). Bispiperidine urea
59 was prepared by acylation of secondary amine 7 with
4-nitrophenyl chloroformate, amination with N-Boc-4,4′-
bipiperidine, ester saponification, and HCl-mediated Boc
removal (Scheme 9).
Biologica l Act ivit y. Nipecotamide analogues of 1
with varied â-substituents on the 3-aminopropionic acid
unit were evaluated in a binding assay involving bioti-
nylated fibrinogen and GPIIb/IIIa, and a functional
assay of human gel-filtered platelet aggregation (nipe-
cotamides 2, 3, 27-41, Table 1). Potent inhibition of
both processes was desired. Relatively optimal potencies
against human gel-filtered platelet aggregation were
The ex vivo results for pyridine analogue 2 were
particularly interesting (Figure 1). Although it is less
potent than 3 functionally in vitro, 2 provided a favor-
able duration of action of 360 min at 3 mg/kg and ca.
300 min at 1 mg/kg, indicative of improved oral absorp-
tion and/or binding to unactivated GPIIb/IIIa (Figure
1). Intravenous administration of 2 (0.3 mg/kg) produced
a duration of action of 300 min, as well. Overall, 2

5258 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Hoekstra et al.
Ta ble 4. Biological Data for Structurally Diverse Pyridyl GPIIb/IIIa Antagonists
human GFPa
IC50 (µΜ)
Fg bindingb
IC50 (nM)
oral duration,c
min (3 mg/kg)
compd
X
Y
n
R1
R2
53
54
55
56
57
58d
59
CH2
CH2
CH2
CH2
NH
CH2CH2
CH2CH2
CH2CH2
(E)-CHdCH
CH2CH2
1
1
1
1
1
0
1
H
Me
H
41
7.2 ( 4.8
0.75 ( 0.54
3.8 ( 0.2
60
90
CHdNH
0.35 ( 0.05
2.2 ( 1.0
0.16 ( 0.04
0.60 ( 0.24
0.14 ( 0.07
0.45
H
H
H
H
H
(CH2)2-c-C6H11
120
210
ND
360
180
H
H
H
H
0.81 ( 0.15
1.7 ( 0.3
CH2
CH2
(E)-CHdCH
4-piperidine
0.58 ( 0.03
0.65 ( 0.55
a
b
Thrombin-induced gel-filtered platelet aggregation (n ) 2). Inhibition of biotinylated fibrinogen binding to immobilized GPIIb/IIIa
(n ) 2). c Oral duration of at least 50% inhibition of ADP-induced platelet aggregation (ex vivo). Racemic pyrrolidine-3-carboxylic acid.
d
Sch em e 6. Synthesis of the Intermediate N-Boc-3-
Sch em e 9. Synthesis of Bipiperidine 59a
(4-piperidine)prop-2-enoic Acida
a
(a) 4-NO2PhOCOCl, NMM, MeCN, N-Boc-4,4′-bipiperidine. (b)
a
(a) Oxalyl-Cl, Et3N, DMSO. (b) Ph3PCHCO2Et, THF. (c) 1 N
LiOH, aq THF. (c) 4 N HCl/dioxane.
NaOH.
Sch em e 7. Synthesis of Bis-Protected Methyl
Piperazine Carboxylate Scaffolda
a
(a) BrCH2CO2Me, THF. (b) H2, Pd-C, EtOH. (c) CBZ-Cl,
iPr2NEt, DCM. (d) BH3, THF. (e) Boc2O, iPr2NEt, CHCl3.
Sch em e 8. Synthesis of Methyl Pyrrolidine-3-
carboxylatea
F igu r e 1. Duration study of inhibition of ADP-induced
platelet aggregation ex vivo following intravenous and oral
dosing of 2 in conscious dogs (n ) 3).
a
(a) BH3, THF. (b) H2, Pd-C, MeOH.
kg, iv. In this assay, while vehicle-treated arteries
occluded in 6-12 min, none of the four animals occluded
over the 30-min observation period when dosed with 3
mg/kg 2. In the ferric chloride arterial injury model,
vehicle-treated guinea pigs occluded in a 12-35 min
period. Intravenous dosing of 2 at 0.3 and 1 mg/kg
inhibited thrombosis dose dependently as well; e.g., four
out of seven animals remained patent at the 60-min
observation point (1 mg/kg).27
exhibited a favorable pharmacokinetic and pharmaco-
dynamic profile with an oral systemic availability of 16
( 8% (AUC method), and intravenous and oral plasma
half-lives of 85 ( 24 min and 114 ( 15 min, respectively.
Furthermore, this compound was well tolerated in that
platelet count, heart rate, and blood pressure remained
normal throughout the experiments.
Intravenous dosing of 2 in three thrombosis models
afforded dose-dependent antithrombotic effects.27 At
cumulative doses of 0.01, 0.03, and 0.1 mg/kg in a canine
arteriovenous shunt model, 2 decreased thrombus weight
from a control of 79 ( 4 mg to 60 ( 8, 31 ( 7, and 12 (
1 mg, respectively. Compound 2 caused a dose-depend-
ent prolongation of time to occlusion of photoactivation-
injured guinea pig carotid artery at 0.3, 1, and 3 mg/
Since relatively optimal pharmacodynamics could be
attributed to the pyridine substituent of 2, substituted
pyridines were prepared by solid-phase parallel syn-
thesis to probe the pyridine-based structure-activity
relationships (Table 2). Since the bulky quinoline â-ami-
no acid of 33 delivered excellent potency, Suzuki cross-
couplings at 5-bromopyridine 15 with arylboronic acids
were conducted to prepare 42b-n . Some improved

Discovery of RWJ -53308
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5259
potencies were observed over the parent compound (42o)
at that position. Racemic bromo (42a ), 3-thienyl (42b),
3-aminophenyl (42e), phenyl (42l), and 2-thienyl (42n )
substituents displayed binding IC50 values of 4 nM or
better. Potency was maintained in the S-enantiomer of
the 5-phenylpyridine analogue (49), and improved with
those with the 5-bromo (44), 5-phenylethynyl (50),
5-phenethyl (51), and 5-ethynyl (52) groups (Table 3).
Oral administration (3 mg/kg) of some of the resolved
pyridines produced good duration against canine ex vivo
platelet aggregation: 44 (210 min) and 51 (180 min).
6-Methylpyridine 43, 6-chloropyridine 45, and 6-(3-
thienyl)pyridine 46 showed comparable potency and
duration as well. Compound 43 exhibited the best
receptor affinity in the pyridine series (IC50 ) 0.13 nM),
along with excellent functional activity (IC50 ) 30 nM).
Because 2 displayed the best pharmacodynamic pro-
file of the antagonists synthesized to this point, the 3S-
(3-pyridyl)-â-amino acid was incorporated into molecules
with other sites of structural diversity as shown in Table
4. For example, methyl (53) and cyclohexylethyl (55)
esters were prepared, albeit with inferior biological
results. N-Formamidinopiperidine 54 lost human anti-
platelet potency (IC50 ) 350 nM) and showed inferior
duration of action ex vivo (90 min) compared to 2.
Olefin-linked N-terminal piperidines maintained good
duration of action ex vivo in both six- (56) and five-
membered (58) scaffold systems, with the latter antago-
nist showing duration equal to 2 (360 min). Bipiperi-
dinyl urea 59 gave satisfactory ex vivo results as well,
although human antiplatelet potency was diminished
(IC50 ) 450 nM). In summary, the relatively robust
activity contributed by the 3S-(3-pyridyl)-â-amino acid
pharmacophore of 2 was observed in other examples as
well (Table 4).
a butylcarbamate group on the R-position of a â-amino
acid.29 This type of pharmacophore is present in the
intravenously administered tirofiban as well.5 Our
studies in this domain of the nipecotamides will be the
subject of a subsequent paper.
Oral administration of 2 at 1 or 3 mg/kg in dogs
resulted in good duration of inhibition of ex vivo platelet
aggregation (5-6 h) without observable platelet count
reduction. Due to the zwitterionic nature of GPIIb/IIIa
antagonists, limited oral absorption has been addressed
by using prodrugs such as xemilofiban and sibrafiban.
To avoid the potential disadvantages of a prodrug such
as metabolic variability, a preliminary objective with
our nipecotamide series was to identify viable, orally
active carboxylic acids. Compound 2, which exhibits
good oral absorption and duration of action at 1 mg/kg,
represents the achievement of that important goal.
Lotrafiban (SB-214857), another non-prodrug GPIIb/
IIIa antagonist, has recently completed phase 2 studies
in humans.30 On the basis of our studies of non-prodrug
nipecotamides,31 pyridine 2 was selected for clinical
evaluation as an antithrombotic agent for both oral and
intravenous administration. RWJ -53308 (2) has now
progressed successfully through human phase 2 clinical
trials. Sequential intravenous and oral administration
of this novel, potent GPIIb/IIIa antagonist could provide
a useful regimen for both acute and chronic antiplatelet
therapy in humans.
Exp er im en ta l Section
In Vitr o P r oced u r es. The in vitro biotinylated fibrinogen/
solid-phase purified GPIIb/IIIa binding assay and the in vitro
inhibition of gel-filtered platelet aggregation assay were
performed as published.14
Ex Vivo Stu d y in Dogs. Mongrel dogs weighing 8-22 kg
(Haycock Farms, PA) and fasted overnight were allowed to
acclimate in isolation cages. A pre-dose blood sample was
drawn from the cephalic vein for platelet aggregation mea-
surements. Compounds, dissolved in 3 mL of saline, were
infused intravenously into the contralateral cephalic vein at
0.3 mg/kg, or administered orally by stomach tube at 1 or 3
mg/kg in 10 mL of water. Blood samples were drawn into
syringes preloaded with sodium citrate at 5, 15, 30, 60, 120,
180, 240, and 360 min after intravenous dosing and at 30, 60,
90, 120, 180, 240, and 360 min after oral dosing. PRP was
collected by centrifugation of whole blood. Platelet count was
determined with a Sysmex K-1000 differential cell counter
(Baxter Laboratories, McGraw, IL) and adjusted to 300 000/
µL by dilution with platelet poor plasma (PPP). A count-
adjusted PRP sample was warmed to 37 °C for 2 min and then
placed in the test well. Aggregation, induced by 20 µM ADP,
was monitored with a Bio-Data platelet aggregometer Model
PAP-4 (Bio-Data Corporation, Horsham, PA). Platelet ag-
gregation was recorded as the increase in light transmission.
The percentage inhibition of aggregation was calculated on the
basis of the difference in percent aggregation in the presence
of drug or vehicle.
P h a r m a cok in etic Stu d ies. Following overnight fast, dogs
in the oral group were administered a single dose of compound
in water (10 mL) by oral gavage followed by water flush (10
mL). Dogs in the intravenous group received a single intra-
venous dose in saline (3 mL) over 30 s. All blood samples (ca.
3 mL) were collected from the jugular vein into heparinized
Vacutainer tubes. Blood samples from the oral group were
collected at 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 h post-dose.
Blood samples from the intravenous group were collected at
0, 0.08, 0.25, 0.5, 1.0, 2.0, 3.0, and 4.0 h post-dose. Plasma
samples were analyzed for plasma concentration of compound
using a validated LCMS assay. Pharmacokinetic analysis was
performed on the plasma concentration data using WinNonlin
Con clu sion
The synthesis and biological evaluation of novel 3-(3-
pyridyl)-â-alanine fibrinogen receptor antagonists rep-
resent an improvement on the pharmacological profile
of nipecotamides related to 3-(3,4-methylendioxyben-
zene)-â-alanine 3. Pyridine 2 is a highly potent, orally
active antiplatelet agent devoid of untoward side effects
in our canine studies. The structure-activity relation-
ships of the nipecotic acid series reported herein bear
some resemblance to the structures related to the
2-piperidone scaffolded L-734217.28 Both series contain
C-terminal â-amino acid and N-terminal piperidine
pharmacophores. However, while a â-methyl substitu-
ent on the â-amino acid was relatively impotent in the
nipecotic acid series,15 a â-methyl in the 2-piperidone
series afforded good potency and a candidate for clinical
development.28 Similarly, Searle has employed a â-ethy-
nyl substituent on the â-amino acid, yet found that a
linear central constraint (succinamide) and an N-
terminal guanidine surrogate (benzamidine) lent good
potency, as in xemilofiban.6b Interestingly, an ethyl ester
of a 3-(3-pyridyl)-â-alanine antagonist from Searle’s
ABAS (aminobenzamidinosuccinyl) series exhibited
thrombocytopenia on oral administration to dogs at 3
mg/kgsa side effect not exhibited by non-prodrug 2 in
dogs.6b In contrast to â-substituted â-amino acid phar-
macophores, the discovery of an isoxazoline-scaffolded
series, which led to the development of roxifiban, placed

5260 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Hoekstra et al.
(Standard Version 1.1, Scientific Consulting, Apex, NC). The
maximum plasma concentration (Cmax, oral), concentration at
time 0 (C0, intravenous), area under the plasma concentration
versus time curve (AUC), clearance (CL/F), terminal half-life
(t1/2), and apparent volume distribution (Vdss) were calculated
as appropriate. Bioavailability (F) of an oral dose of compound
was calculated for each dog using Microsoft Excel (Version 7.0,
Microsoft Corp., Redmond, WA) according to the following
formula:
mol equiv) in MeCN (500 mL) was added HBTU (10.4 g, 1 mol
equiv), HOBT (3.8 g, 1 mol equiv), and NMM (9.2 mL, 3 mol
equiv; NMM ) N-methylmorpholine). This mixture was stirred
for 15 h, diluted with water (30 mL), and evaporated. The
residue was diluted with EtOAc (300 mL), the layers sepa-
rated, and the organic layer was dried (Na2SO4) and evapo-
rated to give a white foam (10.6 g). The foam was treated with
HCl (2 N in dioxane, 60 mL), stirred for 3 h, and evaporated
to 7 as a foam. Compound 7 (9.8 g, 0.027 mol) was dissolved
in MeCN (400 mL), cooled to 5 °C, and treated with N-Boc-4-
piperidinepropanoic acid (6.9 g, 1 mol equiv), HBTU (10.0 g, 1
mol equiv), HOBT (3.6 g, 1 mol equiv), and NMM (8.8 mL, 3
mol equiv) with stirring for 6 h. The mixture was diluted with
water (30 mL), evaporated, and diluted with EtOAc (300 mL),
and the layers separated. The organic layer was dried,
evaporated, and purified by silica gel chromatography (7%
EtOH/DCM) to give a foam (7.3 g). To a solution of the foam
(7.3 g, 0.014 mol) in THF (40 mL) cooled in an ice bath was
added LiOH‚H2O (0.69 g dissolved in 50 mL of water) drop-
wise. This mixture was stirred for 1.5 h, acidified with AcOH
(4.5 mL), and warmed to room temperature. This solution was
diluted with CHCl3 (150 mL) and the layers separated. The
organic layer was dried (Na2SO4) and evaporated to give a
white foam (7.1 g). The foam (7.1 g, 0.014 mol) was dissolved
in dioxane (50 mL) and anisole (1.5 mL), cooled in an ice bath,
treated with HCl (40 mL, 4.0 N in dioxane), and stirred for 3
h to give a precipitate. The precipitate was filtered and washed
with Et2O (300 mL) and MeCN (50 mL) to give 2 as a white
powder (6.1 g): mp 81-89 °C; 1H NMR (DMSO-d6) δ 1.2-2.0
(m, 12 H), 2.3 (m, 3 H), 2.5 (m, 1 H), 2.8 (m, 5 H), 3.2 (d, J )
8 Hz, 2 H), 3.8 (m, 2 H), 4.2 (m, 2 H), 5.2 (m, 1 H), 7.8 (t, J )
4 Hz, 1 H), 8.3 (t, J ) 4 Hz, 1 H), 8.5 (m, 1 H), 8.7 (m, 1 H),
8.9 (m, 2 H); MS m/e 417 (MH+); [R]25D -32.5° (c 0.12, DMSO).
F (%) ) 100(AUCpo/AUCiv)(DOSEiv/DOSEpo
)
Statistical data are expressed as the mean ( the standard
deviation.
Ch em ica l P r oced u r es. High field 1H NMR spectra were
recorded on a Bruker AC-360 spectrometer at 360 MHz with
tetramethylsilane as an internal standard, and coupling
constants are given in hertz (Hz). All mass spectra were
obtained by electrospray technique (MH+) on a Hewlett-
Packard Series 1050 spectrometer. Melting points were de-
termined on a MEL-TEMP II melting point apparatus and are
uncorrected. Microanalyses were performed at Robertson
Microlit Laboratories, Inc., Madison, NJ . Final compounds
were purified by recrystallization/precipitation from common
organic solvents and/or column chromatography using Merck
silica gel 60. Purities were assessed on a combination Waters/
Beckman HPLC System and a Phenomenex Ultra-carb column
(100 × 4.6 mm) using an aqueous TFA/acetonitrile mobile
phase (typically 10% MeCN with 90% water containing 0.1%
TFA); all compounds exhibited >95% purity.
Ma ter ia ls. Arylboronic acids were purchased from Lan-
caster Synthesis, Inc. (R)-Nipecotic acid ethyl ester tartrate
was purchased from Chemi S.P.A. and converted to N-Boc-
(R)-nipecotic acid as published.15 2-Chlorotrityl chloride resin
was purchased from Novabiochem. All other reagents were
purchased from Aldrich Chemical.
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(3,4-m eth ylen ed ioxyp h en yl)]p r op ion ic Acid (3).
Compound 3 was prepared as previously reported15 as a white
powder (1.78 g): mp 190-200 °C; 1H NMR (DMSO-d6) δ 1.2-
1.7 (m, 11 H), 1.81 (d, J ) 10 Hz, 2 H), 2.31 (d, J ) 7 Hz, 2 H),
2.6 (m, 3 H), 2.7 (m, 2 H), 3.0 (m, 1 H), 3.15 (d, J ) 10 Hz, 2
H), 3.7 (m, 1 H), 4.1-4.3 (m, 1 H), 5.08 (dd, J ) 5 Hz, 11, 1
H), 5.95 (s, 2 H), 6.7 (m, 1 H), 6.79 (d, J ) 5 Hz, 1 H), 6.83 (d,
J ) 5 Hz, 1 H), 8.4 (m, 1 H), 8.6 (m, 1 H), 8.9 (m, 1 H), MS m/e
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(3-p yr id yl)]p r op ion ic Acid (2). A mixture of 4
(50.3 g, 0.47 mol), EtOH (1 L), NH4OAc (36.2 g, 1 mol equiv),
and malonic acid (48.9 g, 1 mol equiv) was heated at reflux
for 6 h, cooled, and filtered. The white solid was washed with
EtOH and MeOH and dried. This solid was dissolved in 2:1
acetone/water (360 mL), treated with triethylamine (72.7 g,
0.72 mol) and phenylacetyl chloride (55.6 g, 0.36 mol), and
stirred for 22 h. The mixture was evaporated and the residue
dissolved in water (500 mL) and adjusted to pH 12 (1 N
NaOH). The aqueous layer was adjusted to pH 2 (concentrated
HCl), extracted with Et2O, and evaporated to a white foam.
The foam was purified by silica gel chromatography (10%
MeOH/DCM) to give 5 (DCM ) CH2Cl2). A solution of
compound 5 (62.5 g, 0.22 mol) in water (600 mL) at room
temperature was adjusted to pH 7.5 using KOH (3.0 N) and
treated with penicillin amidase (91 520 units, Sigma).20 This
mixture was stirred for 47 h, acidified to pH 1 with HCl
(concentrated), and the resultant precipitate filtered through
Celite. The filtrate was extracted with Et2O (3 × 300 mL),
concentrated in vacuo, and treated with MeOH/concentrated
NH4OH (9:1). This product-containing solution was purified
by silica gel chromatography (eluent DCM/MeOH/NH4OH, 78:
18:4) to give (S)-3-phenylacetamido-3-(3-pyridyl)propionic acid
ammonium salt (19.5 g). This product was treated with HCl
(6.0 N, 292 mL), heated at reflux for 5 h, cooled to 23 °C, and
extracted with Et2O (3 × 200 mL). The aqueous layer was
adjusted to pH 12, concentrated in vacuo, and the resultant
solid triturated with MeOH (2 × 300 mL). This solution was
evaporated to give ca. 14 g of sodium salt. This material was
treated with MeOH (500 mL), 2,2-dimethoxypropane (44 mL),
and HCl (4 N in dioxane, 84 mL), and stirred for 90 h at 23
°C. This mixture was filtered and the filtrate concentrated in
vacuo. The resultant off-white solid was triturated with Et2O
(2 × 150 mL) and dried to give 6 (16.7 g, 96% enantiomeric
excess) as a white, amorphous solid. To a cooled (5 °C) solution
of N-Boc-(R)-nipecotic acid (6.3 g, 0.028 mol) and 6 (7.0 g, 1
460 (MH+); [R]25 -0.478° (c 1.00, MeOH).
D
N-3-(4-N-Meth ylp ip er id in ep r op ion yl)-(R)-(-)-n ip eco-
tyl[(S)-3-a m in o-3-(3,4-m eth ylen ed ioxyp h en yl)]p r op ion -
ic Acid (27). Compound 27 was prepared as described for 2,
except N-Me-4-piperidinepropanoic acid was employed in the
second coupling step (57% yield; see Scheme 1, step h) to give
a tan powder (0.76 g): 1H NMR (CD3OD) δ 1.3-2.0 (m, 11 H),
2.4 (m, 3 H), 2.7 (m, 2 H), 2.84 (s, 3 H), 3.0 (m, 3 H), 3.2 (m, 1
H), 3.50 (d, J ) 7 Hz, 2 H), 3.8 (m, 1 H), 4.3 (m, 1 H), 5.22 (t,
J ) 3 Hz, 1 H), 5.90 (s, 2 H), 6.8 (m, 3 H), 8.2-8.4 (m, 3 H);
MS m/e 474 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
am in o-3-(3,4-m eth ylen edioxyph en yl)]pr opion ic Acid Eth -
yl Ester (28). Compound 28 was prepared as previously
reported15 except the lithium hydroxide ester saponification
step was omitted, to give a white powder (1.34 g): MS m/e
488 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(R)-3-
a m in o-3-(2-p h en ylet h yn yl)]p r op ion ic Acid (29). Com-
pound 29 was prepared as described for 2, except methyl [(R)-
3-amino-3-(2-phenylethynyl)] propionate6b was employed in the
first coupling step (77% yield; see Scheme 2) to give a white
powder (1.25 g): 1H NMR (DMSO-d6) δ 1.1-1.9 (m, 10 H), 2.3
(m, 3 H), 2.7 (m, 5 H), 3.2 (m, 3 H), 3.4 (m, 2 H), 3.8 (m, 1 H),
4.3 (m, 1 H), 5.1 (m, 1 H), 7.36 (s, 5 H), 8.8 (m, 3 H); MS m/e
440 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(2-p h en ylet h yn yl)]p r op ion ic Acid (30). Com-
pound 30 was prepared as described for 2, except methyl [(S)-
3-amino-3-(2-phenylethynyl)]propionate6b was employed in the
first coupling step (80% yield; see Scheme 2) to give a white
powder (0.76 g): MS m/e 440 (MH+).

Discovery of RWJ -53308
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5261
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl-[(R)-3-
a m in o-3-(2-ter t-bu tyleth yn yl)]p r op ion ic Acid (31). Com-
pound 31 was prepared as described for 2, except methyl [(R)-
3-amino-3-(2-tert-butylethynyl)]propionate6b was employed in
the first coupling step (72% yield; see Scheme 2) to give a white
powder (0.12 g): 1H NMR (CD3OD) δ 1.19 (s, 9 H), 1.3-2.0
(m, 11 H), 2.5 (m, 3 H), 2.6 (m, 2 H), 2.9 (m, 4 H), 3.4 (m, 3 H),
3.9 (m, 1 H), 4.2 (m, 1 H), 4.5 (m, 1 H), 4.8 (m, 2 H), 5.0 (t, J
) 3 Hz, 1 H); MS m/e 420 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(2-ter t-bu tyleth yn yl)]p r op ion ic Acid (32). Com-
pound 32 was prepared as described for 2, except methyl [(S)-
3-amino-3-(2-tert-butylethynyl)] propionate6b was employed in
the first coupling step (81% yield; see Scheme 2) to give a white
powder (0.33 g): 1H NMR (CD3OD) δ 1.21 (s, 9 H), 4.9 (m, 1
H); MS m/e 420 (MH+).
methyl (R,S)-2-hydroxy-3-aminopropionate, and was isolated
as the TFA salt: pink glass (0.050 g): 1H NMR (DMSO-d6) δ
1.0-1.4 (m, 10 H), 1.8 (m, 4 H), 2.2 (m, 3 H), 2.6 (m, 1 H), 2.8
(m, 3 H), 3.2 (m, 3 H), 3.7 (m, 1 H), 4.2 (m, 2 H), 7.6 (m, 1 H),
8.2 (m, 1 H), 8.5 (m, 1 H); MS m/e 356 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(3-ch lor o-5-tr iflu or om eth yl-2-p yr id yl)]p r op ion -
ic Acid (41). Compound 41 was prepared as described for 2,
except methyl(S)-3-amino-3-(3-chloro-5-trifluoromethyl-2-py-
ridyl)propionate (prepared by kinetic resolution of the (-)-
ephedrine salt of N-Boc-3-amino-3-(3-chloro-5-trifluoromethyl-
2-pyridyl)propionic acid as for 43) was employed in the first
coupling step (97% yield; see Scheme 1) to give a white foam
(1.72 g): mp 78-80 °C; MS m/e 519 (MH+); [R]25 -50.2° (c
D
0.22, MeOH).
Rep r esen ta tive Solid -P h a se Syn th esis for 42b-n : N-3-
(4-P ip er id in ep r op ion yl)n ip ecotyl[3-a m in o-3-(5-p h en yl-
3-p yr id yl)]p r op ion ic Acid (42l). A 25 mL sintered-glass
vessel under nitrogen was charged with 2-chlorotrityl chloride
resin (0.24 g, 0.36 mmol, Novabiochem) and DMF (5 mL). The
resin was agitated and swelled with nitrogen for 5 min and
the DMF removed. The resin was treated with DMF (5 mL),
DIPEA (0.31 mL, 5 mol equiv), and allyl 3-(4-piperidine)-
propionate‚HCl (0.20 g, 2.4 mol equiv), sequentially, and
agitated for 8 h. The resultant dark green solution was
removed, and the resin washed with DMF (3 × 5 mL), aqueous
DMF (25%, 3 × 5 mL), THF (3 × 5 mL), DCM (3 × 5 mL), and
Et2O (5 mL). The resin was swelled with DCE (5 mL; DCE )
ClCH2CH2Cl) and treated with a mixture of tetrabutylammo-
nium fluoride hydrate (0.28 g, 3 mol equiv), azidotrimethyl-
silane (0.38 mL, 10 mol equiv), tetrakis(triphenylphosphine)-
palladium (0.084 g, 20 mol %), and DCE (5 mL). The resin
was agitated for 15 h and the orange solution removed. The
resin was washed with DCM (3 × 5 mL), DMF (3 × 5 mL),
THF (3 × 5 mL), and Et2O (5 mL). The resin was swelled with
DMF (5 mL) and treated with DIPEA (0.18 mL, 3 mol equiv),
racemic allyl nipecotate‚HCl (0.17 g, 3 mol equiv), DIC (0.17
mL, 3 mol equiv; DIC ) diisopropylcarbodiimide), and HOBT
(1 mg). The resin was agitated for 15 h and then the reaction
solution removed. The resin was washed with DMF (3 × 5 mL),
aqueous DMF (25%, 3 × 5 mL), THF (3 × 5 mL), DCM (3 × 5
mL), and Et2O (5 mL). The resin was swelled with DCE (5
mL) and treated with a mixture of tetrabutylammonium
fluoride hydrate (0.28 g, 3 mol equiv), azidotrimethylsilane
(0.38 mL, 10 mol equiv), tetrakis(triphenylphosphine)pal-
ladium (0.084 g, 0.02 mol equiv), and DCE (5 mL). The resin
was agitated for 15 h and the orange solution removed. The
resin was washed with DCM (3 × 5 mL), DMF (3 × 5 mL),
THF (3 × 5 mL), and Et2O (5 mL). The resin was swelled with
DMF (5 mL) and treated with DIEA (0.18 mL, 3 mol equiv),
methyl d,L-3-amino-3-(5-bromopyridyl)propionate‚HCl (0.36 g,
3 mol equiv), DIC (0.17 mL, 3 mol equiv), and HOBT (1 mg).
The resin was agitated for 17 h and then the reaction solution
removed. The resin was washed with DMF (3 × 5 mL),
aqueous DMF (25%, 3 × 5 mL), THF (3 × 5 mL), DCM (3 × 5
mL), and Et2O (5 mL). The resin was transferred to a round-
bottomed flask, swelled with DME (5 mL; DME ) MeOCH2-
CH2OMe), treated with phenylboronic acid (0.09 g, 2 mol equiv)
and aqueous sodium carbonate (0.45 mL, 2.0 M), and heated
at 65 °C for 18 h. This mixture was cooled, the reaction solution
removed, and the resin washed with DMF (3 × 5 mL), aqueous
DMF (25%, 3 × 5 mL), THF (3 × 5 mL), DCM (3 × 5 mL), and
Et2O (5 mL). The resin was swelled with THF (5 mL) and
treated with a solution of KOTMS (0.23 g, 10 mol equiv) and
THF (2 mL). The resin was agitated for 18 h and then the
reaction solution removed. The resin was washed with DMF
(3 × 5 mL), HOAc/THF (1:1, twice), aqueous DMF (25%, 3 ×
5 mL), THF (3 × 5 mL), DCM (3 × 5 mL), and Et2O (5 mL).
The resin was treated with TFA/DCM (1:1, 10 mL), agitated
for 15 min, and the resultant red solution collected. This
solution was evaporated and the resultant oil triturated with
Et2O (3 × 5 mL) and dried to afford compound 42l as a clear
glass (0.045 g, 17%): 1H NMR (CD3OD) δ 1.1-1.7 (m, 10 H),
1.8 (m, 4 H), 2.4 (m, 3 H), 2.6 (m, 1 H), 2.9 (m, 4 H), 3.2 (d, J
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(3-qu in olin yl)]p r op ion ic Acid (33). Compound 33
was prepared as described for 2, except methyl (S)-3-amino-
3-(3-quinolinyl)propionate (prepared by penicillin amidase
resolution as for 2) was employed in the first coupling step
(65% yield; see Scheme 1) to give white flakes (1.11 g): mp
142-144 °C; MS m/e 467 (MH+); [R]25D -173° (c 1.00, MeOH).
N-3-(4-P ip er id in ep r op ion yl)-(S)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(3-qu in olin yl)]p r op ion ic Acid (34). Compound 34
was prepared as described for 2, except methyl (S)-3-amino-
3-(3-quinolinyl)propionate (prepared by penicillin amidase
resolution as for 2) was employed in the first coupling step
with N-Boc-(S)-nipecotic acid (71% yield; see Scheme 1) to give
a white solid (0.057 g): MS m/e 467 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(2-th ien yl)]p r op ion ic Acid (35). Compound 35 was
prepared as described for 2, except methyl (S)-3-amino-3-(2-
thienyl) propionate (prepared by penicillin amidase resolution
as for 2) was employed in the first coupling step with N-Boc-
(R)-nipecotic acid (38% yield; see Scheme 1) to give a glass
(0.093 g): mp 99-109 °C; MS m/e 422 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(5-ch lor o-2-th ien yl)]p r op ion ic Acid (36). Com-
pound 36 was formed as a byproduct during the final HCl/
dioxane-mediated Boc removal step during the synthesis of
35, isolated by reverse phase HPLC (gradient 5-50% MeCN/
0.1%TFA/water on a C18 column), and converted to the HCl
salt using 1 N HCl to give a glass (0.12 g): mp 94-105 °C;
MS m/e 457 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl-(R)-3-
a m in obu tyr ic Acid (37). Compound 37 was prepared on a
2-chlorotrityl resin support as reported15 using tert-butyl (R)-
3-aminobutyrate (purchased from Oxford Asymmetry) and was
isolated as a tan powder (0.050 g, TFA salt): 1H NMR (CD3-
OD) δ 1.17 (d, J ) 9 Hz, 3 H), 1.3 (m, 2 H), 1.5 (m, 6 H), 1.7
(m, 2 H), 2.0 (m, 2 H), 2.4 (m, 2 H), 2.7 (m, 2 H), 2.9 (m, 3 H),
3.2 (m, 1 H), 3.3 (m, 3 H), 3.5 (m, 2 H), 3.9 (m, 1 H), 4.2 (m, 1
H), 4.5 (m, 1 H); MS m/e 354 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl-(R)-3-
a m in o-4-p h en ylbu tyr ic Acid (38). Compound 38 was pre-
pared on a 2-chlorotrityl resin support as reported15 using tert-
butyl (R)-3-amino-4-phenylbutyrate (purchased from Oxford
Asymmetry) and was isolated as a tan glass (0.030 g, TFA
salt): 1H NMR (DMSO-d6) δ 1.3 (m, 2 H), 1.5 (m, 6 H), 1.7 (m,
2 H), 2.1 (m, 2 H), 2.4 (m, 2 H), 2.7 (m, 2 H), 2.9 (m, 3 H), 3.0
(d, J ) 5 Hz, 2 H), 3.2 (m, 1 H), 3.3 (m, 2 H), 3.5 (m, 2 H), 3.9
(m, 1 H), 4.2 (m, 1 H), 4.5 (m, 1 H) 7.1 (m, 5 H), 8.0 (m, 2 H);
MS m/e 430 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecotyl[(2S)-h y-
d r oxy-(3R)-a m in o-4-p h en yl]bu tyr ic Acid (39). Compound
39 was prepared as described for 2, except tert-butyl [(2S)-
hydroxy-(3R)-amino-4-phenyl]butyrate (purchased from Oxford
Asymmetry), was employed in the first coupling step with
N-Boc-(R)-nipecotic acid (99% yield; see Scheme 1) to give a
white foam (2.07 g): mp 73-77 °C; MS m/e 446 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecotyl[(R,S)-2-
h yd r oxy-3-a m in o]p r op ion ic Acid (40). Compound 40 was
prepared on a 2-chlorotrityl resin support as reported15 using

5262 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Hoekstra et al.
) 5 Hz, 2 H), 3.8 (d, J ) 5 Hz, 1 H), 4.2 (m, 1 H), 5.4 (m, 1 H),
7.5 (m, 5 H), 8.1 (d, J ) 8 Hz, 1 H), 8.5 (d, J ) 3 Hz, 1 H), 8.7
(m, 3 H), 9.0 (m, 1 H).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(5-br om o-3-p yr id yl)]p r op ion ic Acid (44). Com-
pound 44 was prepared as shown in Scheme 1. The â-amino
acid was resolved by kinetic resolution of racemic N-Boc-3-
amino-3-(5-bromo-3-pyridyl)]propionic acid as described for 43
(35% yield). Compound 44 was isolated as a white foam (1.24
g): mp 98-101 °C; MS m/e 495 and 497 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(6-ch lor o-3-p yr id yl)]p r op ion ic Acid (45). Com-
pound 45 was prepared as shown in Scheme 1. The â-amino
acid was resolved by kinetic resolution of racemic N-Boc-3-
amino-3-(6-chloro-3-pyridyl)]propionic acid as described for 43
(38% yield). Compound 45 was isolated as white flakes (1.54
g): mp 101-105 °C; MS m/e 451 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
am in o-3-(6-(3-th ien yl)-3-pyr idyl)]pr opion ic Acid (46). Com-
pound 46 was prepared as shown in Scheme 1. The â-amino
ester was prepared as follows. Methyl (S)-N-Boc-3-amino-3-
(6-chloro-3-pyridyl)]propionate (1.4 g, 0.0043 mol, see 45) in
THF (65 mL) was treated with 3-thiopheneboronic acid (0.60
g, 1.1 mol equiv), tetrakis(triphenylphosphine)palladium (0.25
g, 0.05 mol equiv), and K2CO3 (0.59 g, 1 mol equiv) and the
resultant solution was heated at reflux for 18 h. The reaction
was cooled, filtered, and diluted with DCM (130 mL) and
saturated NH4Cl (20 mL), and the layers separated. The
organic layer was dried (Na2SO4) and evaporated to afford a
dark green oil (1.51 g, 97%). The Boc group was removed with
HCl (see 2) to give methyl (S)-3-amino-3-(6-(3-thienyl)-3-
pyridyl)]propionate (1.34 g), and the synthesis was completed
as shown in Scheme 1. Compound 46 was isolated as a white
foam (1.05 g): mp 110-114 °C; MS m/e 499 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
am in o-3-(5,6-dich lor o-3-pyr idyl)]pr opion ic Acid (47). Com-
pound 47 was prepared as shown in Scheme 1. The â-amino
acid was resolved by kinetic resolution of racemic N-Boc-3-
amino-3-(5,6-dichloro-3-pyridyl)]propionic acid as described for
43 (41% yield). Compound 47 was isolated as a white powder
(1.28 g): mp 128-130 °C; MS m/e 486 (MH+).
Using the same general solid-phase synthesis technique as
described for 42l, compounds 42a -o were prepared as shown
in Scheme 4. All compounds gave satisfactory mass spectral
analysis. Representative compounds gave satisfactory 1H NMR
spectra (five compounds per matrix). Products exhibited puri-
ties of 90-99%.15
N-3-(4-P ip er id in ep r op ion yl)n ip ecot yl[3-a m in o-3-(5-
1
br om o-3-p yr id yl)]p r op ion ic Acid (42a ). H NMR (DMSO-
d6) δ 1.0-1.7 (m, 10 H), 1.8 (m, 4 H), 2.3 (m, 3 H), 2.5 (m, 1
H), 2.7 (m, 4 H), 3.2 (d, J ) 5 Hz, 2 H), 3.8 (d, J ) 5 Hz, 1 H),
4.2 (m, 1 H), 5.2 (m, 1 H), 7.9 (d, J ) 8 Hz, 1 H), 8.5 (d, J ) 3
Hz, 1 H), 8.7 (m, 3 H), 9.0 (m, 1 H).
N-3-(4-P ip er id in ep r op ion yl)n ip ecotyl[3-a m in o-3-(5-(2-
1
ben zofu r a n yl)-3-p yr id yl)]p r op ion ic Acid (42c). H NMR
(CD3OD) δ 1.1-1.7 (m, 10 H), 1.8 (m, 4 H), 2.4 (m, 3 H), 2.6
(m, 1 H), 2.9 (m, 4 H), 3.2 (d, J ) 5 Hz, 2 H), 3.8 (d, J ) 5 Hz,
1 H), 4.2 (m, 1 H), 5.4 (m, 1 H), 7.2-7.5 (m, 4 H), 7.6 (d, J )
6 Hz, 1 H), 8.1 (d, J ) 8 Hz, 1 H), 8.3 (d, J ) 3 Hz, 1 H), 8.7
(m, 3 H), 9.1 (m, 1 H).
N-3-(4-P ip er id in ep r op ion yl)n ip ecotyl[3-a m in o-3-(5-(3-
m eth oxyp h en yl)-3-p yr id yl)]p r op ion ic Acid (42f). 1H NMR
(CD3OD) δ 1.1-1.7 (m, 10 H), 1.8 (m, 4 H), 2.4 (m, 3 H), 2.6
(m, 1 H), 2.9 (m, 4 H), 3.2 (d, J ) 5 Hz, 2 H), 3.8 (d, J ) 5 Hz,
1 H), 3.91 (s, 3 H), 4.2 (m, 1 H), 5.4 (m, 1 H), 7.1 (m, 2 H), 7.3
(m, 2 H), 8.0 (d, J ) 8 Hz, 1 H), 8.5 (d, J ) 3 Hz, 1 H), 8.7 (m,
3 H), 9.2 (m, 1 H).
N-3-(4-P ip er id in ep r op ion yl)n ip ecotyl[3-a m in o-3-(5-(2-
m eth oxyp h en yl)-3-p yr id yl)]p r op ion ic Acid (42j). 1H NMR
(CD3OD) δ 1.1-1.7 (m, 10 H), 1.8 (m, 4 H), 2.4 (m, 3 H), 2.6
(m, 1 H), 2.9 (m, 4 H), 3.2 (d, J ) 5 Hz, 2 H), 3.8 (d, J ) 5 Hz,
1 H), 3.88 (s, 3 H), 4.2 (m, 1 H), 5.4 (m, 1 H), 7.0 (m, 2 H), 7.4
(m, 2 H), 8.0 (d, J ) 8 Hz, 1 H), 8.6 (d, J ) 3 Hz, 1 H), 8.7 (m,
3 H), 9.0 (m, 1 H).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(6-m eth yl-3-p yr id yl)]p r op ion ic Acid (43). Com-
pound 43 was prepared as shown in Schemes 1 and 3. The
â-amino acid was resolved by kinetic resolution of racemic
N-Boc-3-amino-3-(6-methyl-3-pyridyl)]propionic acid.6b For the
resolution, racemic 3-amino-3-(6-methyl-3-pyridyl)]propionic
acid (5.2 g, 0.029 mol), prepared as described for compound 2
in 61% yield, was dissolved in sodium hydroxide (1 N, 60 mL)
and 1,4-dioxane (35 mL) treated with di-tert-butyl dicarbonate
(6.5 g, 1 mol equiv), and stirred at 23 °C for 3 h. The dioxane
was removed in vacuo, the aqueous layer was washed with
hexane (50 mL), and the layers separated. The aqueous layer
was acidified with citric acid (7 g) and extracted with chloro-
form (6 × 50 mL). The combined organic solutions were dried
(Na2SO4) and evaporated to afford N-Boc-3-amino-3-(6-methyl-
3-pyridyl)]propionic acid (3.9 g, 48%) as a white powder. To a
slurry of the powder in EtOAc (170 mL) was added a solution
of (1R,2S)-(-)-ephedrine (2.3 g, 1 mol equiv) in EtOAc (170
mL). This mixture was heated to reflux to afford a clear
solution; the solution was allowed to cool to room temperature
and was filtered. The filtered white solid was washed with
EtOAc (50 mL) and Et2O (50 mL) and dried to afford (S)-N-
Boc-3-amino-3-(6-methyl-3-pyridyl)]propionic acid‚(-)-ephe-
drine as a white powder (1.9 g, 31%, mp 152.5-153.0 °C). This
powder was dissolved in 1 N sodium hydroxide (5.2 mL), it
was washed with DCM (2 × 30 mL), and the layers were
separated. The aqueous layer was acidified with citric acid (4
g) and extracted with chloroform (6 × 40 mL). The combined
organic solutions were dried (Na2SO4) and evaporated to give
white flakes. The flakes were dissolved in 4 N HCl in dioxane
(10 mL), MeOH (25 mL), and 2,2-dimethoxypropane (1.0 mL)
and stirred for 22 h at 23 °C. The solution was evaporated,
triturated with Et2O (100 mL), and dried to afford methyl (S)-
3-amino-3-(6-methyl-3-pyridyl)]propionate‚2HCl (14) as a tan
foam (2.0 g). The foam was employed as described for com-
pound 2 to prepare target 43 as a white foam (1.20 g): mp
99-105 °C; MS m/e 431 (MH+); UV (MeOH) λmax 269 nm.
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(5-ch lor o-6-m eth oxy-3-p yr id yl)]p r op ion ic Acid
(48). Compound 48 was prepared as shown in Scheme 1. The
â-amino acid was resolved by kinetic resolution of racemic
N-Boc-3-amino-3-(5-chloro-6-methoxy-3-pyridyl)]propionic acid
as described for 43 (41% yield). Compound 48 was isolated as
a white foam (0.50 g): mp 145-151 °C; MS m/e 481 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(5-p h en yl-3-p yr id yl)]p r op ion ic Acid (49). Com-
pound 49 was prepared as shown in Scheme 1. The methyl
(S)-3-amino-3-(5-phenyl-3-pyridyl)]propionate intermediate was
prepared as described for 46 (81% yield, Suzuki coupling with
phenylboronic acid). Compound 49 was isolated as a white
foam (0.88 g): 1H NMR (CD3OD) δ 1.2-1.8 (m, 11 H), 2.0 (m,
3 H), 2.4 (m, 2 H), 2.6 (m, 4 H), 2.9 (m, 2 H), 3.3 (m, 3 H), 3.8
(m, 1 H), 4.3 (m, 1 H), 5.4 (m, 1 H), 7.4 (m, 1 H), 7.5 (t, J ) 7
Hz, 2 H), 7.7 (d, J ) 7 Hz, 2 H), 8.1 (m, 1 H), 8.50 (s, 1 H),
8.64 (s, 1 H); MS m/e 493 (MH+); UV (MeOH) λmax 249 nm.
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl-[(S)-3-
a m in o-3-(5-p h en eth yn yl-3-p yr id yl)]p r op ion ic Acid (50).
Compound 50 was prepared as shown in Scheme 1. Intermedi-
ate 18a was prepared as described for 18b (see 52); the methyl
(S)-3-amino-3-(5-phenethynyl-3-pyridyl)]propionate intermedi-
ate was prepared/resolved as described for 43. Compound 50
was isolated as a white foam (0.44 g): 1H NMR (CD3OD) δ
1.3-1.9 (m, 11 H), 2.0 (m, 3 H), 2.4 (m, 2 H), 2.6 (m, 4 H), 2.9
(m, 2 H), 3.3 (m, 3 H), 3.8 (m, 1 H), 4.3 (m, 1 H), 5.4 (m, 1 H),
7.4 (m, 3 H), 7.7 (d, J ) 7 Hz, 2 H), 8.6 (m, 2 H), 8.8 (m, 2 H);
MS m/e 517 (MH+); UV (MeOH) λmax 281 nm.
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
am in o-3-(5-ph en eth yl-3-pyr idyl)]pr opion ic Acid (51). Com-
pound 51 was prepared as shown in Scheme 1. The methyl
(S)-3-amino-3-(5-phenethyl-3-pyridyl)]propionate intermediate
(19b) was prepared by hydrogenation of 19a over 5% pal-
ladium-on-carbon in MeOH at 50 psig and 23 °C (96% yield).
Compound 51 was isolated as white flakes (0.25 g): 1H NMR

Discovery of RWJ -53308
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25 5263
(CD3OD) δ 1.3-1.9 (m, 11 H), 2.0 (m, 7 H), 2.4 (m, 2 H), 2.6
(m, 4 H), 2.9 (m, 2 H), 3.3 (m, 3 H), 3.8 (m, 1 H), 4.3 (m, 1 H),
5.3 (m, 1 H), 7.4 (m, 3 H), 7.7 (d, J ) 7 Hz, 2 H), 8.3 (m, 1 H),
8.42 (s, 1 H), 8.72 (s, 1 H), 8.8 (m, 1 H); MS m/e 521 (MH+);
UV (MeOH) λmax 269 nm.
EDC‚HCl (0.44 g, 2 mol equiv), stirred for 8 h, and diluted
with satd NH4Cl (10 mL). The layers were separated, and the
organic layer was dried (Na2SO4), evaporated, and purified by
flash column chromatography (1% NH4OH/8% EtOH/DCM) to
afford of 2-cyclohexylethyl N-Boc-3-(4-piperidine-propionyl)-
(R)-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)]propionate (0.45 g,
62%). This ester was deprotected with HCl (see 2), and 55 was
isolated as a white foam (0.26 g): mp 88-95 °C; 1H NMR
(DMSO-d6) δ 0.9 (m, 2 H), 1.1-1.3 (m, 10 H), 1.4-1.9 (m, 10
H), 2.3 (m, 3 H), 2.5 (m, 1 H), 2.8 (m, 4 H), 3.2 (d, J ) 8 Hz, 2
H), 3.60 (s, 3 H), 3.8 (m, 2 H), 4.0 (t, J ) 4 Hz, 2 H), 4.2 (m, 2
H), 5.3 (m, 1 H), 7.9 (t, J ) 4 Hz, 1 H), 8.4 (t, J ) 4 Hz, 1 H),
8.6 (m, 1 H), 8.7 (m, 1 H), 8.9 (m, 2 H); MS m/e 527 (MH+);
UV (MeOH) λmax 261 nm.
N-3-(4-P ip er id in ep r op -2-en oyl)-(R)-(-)-n ip ecot yl[(S)-
3-a m in o-3-(3-p yr id yl)]p r op ion ic Acid (56). Compound 56
was prepared as shown in Scheme 1. N-Boc-3-(4-piperidine)-
prop-2-enoic acid was prepared as follows. To a solution of
oxalyl chloride (24.8 mL, 50 mmol) in DCM (200 mL) at -78
°C was added DMSO (7.0 mL) dropwise. The mixture was
stirred for 30 min, treated with N-Boc-4-piperidinemethanol
(8.2 g, 0.038 mol), and stirred for 2 h. Triethylamine (31.7 mL,
6 mol equiv) was added dropwise, the mixture was warmed to
23 °C, and the mixture was diluted with water (30 mL). The
layers were separated; the organic layer was washed with
saturated NH4Cl (30 mL) and saturated NaCl (30 mL), dried
(Na2SO4), evaporated, and purified by silica gel chromatogra-
phy (20% EtOAc/hexane) to give a white solid (7.3 g, 34 mmol).
A solution of ethyl 2-(triphenylphosphoranylidene)acetate (13.1
g, 0.038 mol) and DCM (40 mL) at 5 °C was treated with this
white solid (7.3 g), warmed to 23 °C, stirred for 2.5 h, and
evaporated to dryness. This solid was treated with pentane
(50 mL), and triphenylphosphine oxide was removed by
filtration. The pentane solution was concentrated and the solid
purified by silica gel chromatography (10% EtOAc/hexane) to
afford a glass (8.4 g). The glass was dissolved in EtOH (60
mL), and this solution was treated with water (60 mL) and 1
N sodium hydroxide (59 mL) at 23 °C. The mixture was stirred
for 4 h, acidified with citric acid (8 g), and extracted with DCM
(3 × 100 mL). The combined organics were dried (Na2SO4) and
evaporated to give N-Boc-3-(4-piperidine)prop-2-enoic as a
white solid acid (7.5 g, 0.029 mol, 76% overall yield). This solid
was reacted with 7 as shown in Scheme 1. Compound 56 was
isolated as a foam (0.86 g): 1H NMR (DMSO-d6) δ 1.2-2.0 (m,
10 H), 2.3 (m, 1 H), 2.5 (m, 1 H), 2.8 (m, 5 H), 3.2 (d, J ) 8 Hz,
2 H), 3.8 (m, 2 H), 4.2 (m, 2 H), 5.2 (m, 1 H), 6.5 (m, 2 H), 8.0
(t, J ) 4 Hz, 1 H), 8.5 (d, J ) 5 Hz, 1 H), 8.8 (d, J ) 4 Hz, 1
H), 8.9 (m, 3 H); MS m/e 414 (MH+).
N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecot yl[(S)-3-
a m in o-3-(5-eth yn yl-3-p yr id yl)]p r op ion ic Acid (52). Com-
pound 52 was prepared as shown in Scheme 1. The synthesis
of 18b was carried out as follows. A solution of ethyl 5-bro-
monicotinate (38 g, 0.16 mol), triethylamine (69 g, 4.3 mol
equiv), and EtOAc (150 mL) was degassed with nitrogen for
15 min, treated with trimethylsilylacetylene (75 g, 4.8 mol
equiv), bis(triphenylphosphine)palladium chloride (0.56 g, 0.05
mol equiv), and copper iodide (0.30 g, 0.01 mol equiv), and
stirred at 50 °C for 9 h. This dark mixture was cooled, filtered
through Celite, and evaporated to give a dark brown oil. The
oil was dissolved in EtOH (500 mL), treated with K2CO3 (1.6
g), and stirred for 20 h at 23 °C. The solvent was evaporated,
and the dark residue was treated with water (150 mL) and
extracted with EtOAc (3 × 300 mL). The combined organics
were dried (Na2SO4) and evaporated to give dark brown
crystals. The crystals were dissolved in EtOAc/hexane (9:1, 500
mL) and filtered through silica gel (300 mL), and the solvent
evaporated to give yellow crystals (26 g, 93% for two steps).
The crystals were dissolved in THF (600 mL), and this solution
cooled to -78 °C. The solution was treated with lithium
aluminum hydride (6.2 g, 1.1 mol equiv), stirred for 4 h, and
quenched with dropwise addition of water (50 mL). This
mixture was warmed to 23 °C, filtered through Celite, and
evaporated. The resultant red oil was dissolved in THF/DCM
(1:1, 300 mL), treated with charcoal, filtered, and evaporated
to give an orange solid (15.4 g). A solution of the solid in DCM
(400 mL) at room temperature was treated with pyridinium
dichromate (40 g, 0.11 mol), stirred for 22 h, and filtered
through silical gel (300 g). The filtrate was evaporated to give
18b as a white solid (7.0 g, 46% yield). The methyl (S)-3-amino-
3-(5-ethynyl-3-pyridyl)]propionate intermediate was prepared/
resolved as described for 43. Compound 52 was isolated as a
tan foam (0.15 g): 1H NMR (CD3OD) δ 1.3-1.8 (m, 10 H), 2.0
(m, 7 H), 2.4 (m, 2 H), 2.5 (m, 3 H), 2.9 (m, 2 H), 3.3 (m, 3 H),
3.8 (m, 1 H), 4.1 (m, 1 H), 4.31 (s, 1 H), 5.4 (m, 1 H), 8.64 (s,
1 H), 8.87 (s, 1 H), 8.92 (s, 1 H); MS m/e 441 (MH+).
Meth yl N-3-(4-P ip er id in ep r op ion yl)-(R)-(-)-n ip ecotyl-
[(S)-3-a m in o-3-(3-p yr id yl)]p r op ion a te (53). Compound 53
was prepared as shown in Scheme 1 for 2, with omission of
saponification step I. Compound 53 was isolated as white
1
flakes (0.56 g): mp 75-80 °C; H NMR (DMSO-d6) δ 1.2-1.9
(m, 11 H), 2.3 (m, 3 H), 2.5 (m, 1 H), 2.8 (m, 5 H), 3.2 (d, J )
8 Hz, 2 H), 3.60 (s, 3 H), 3.8 (m, 2 H), 4.2 (m, 2 H), 5.3 (m, 1
H), 7.9 (t, J ) 4 Hz, 1 H), 8.4 (t, J ) 4 Hz, 1 H), 8.6 (m, 1 H),
8.7 (m, 1 H), 9.0 (m, 2 H); MS m/e 431 (MH+); UV (MeOH)
λmax 261 nm.
N-3-(4-P ip er id in ep r op ion yl)-(4R)-(+)-p ip er a zin e-2-ca r -
bon yl[(S)-3-am in o-3-(3-pyr idyl)]pr opion ic Acid (57). Meth-
yl 1-N-Boc-(R)-(+)-piperazine-2-carboxylate was prepared by
the method of B. Aebischer,25 coupled with N-Boc-3-(4-pip-
eridine)propionic acid, saponified, and coupled with the ap-
propriate â-amino ester as described for 2. Compound 57 was
isolated as a white powder (0.079 g): 1H NMR (DMSO-d6) δ
1.2-2.0 (m, 10 H), 2.3 (m, 3 H), 2.6 (m, 1 H), 2.8 (m, 5 H), 3.2
(d, J ) 8 Hz, 2 H), 3.8 (m, 2 H), 4.2 (m, 2 H), 5.5 (m, 1 H), 8.0
(m, 1 H), 8.4 (m, 1 H), 8.6 (m, 1 H), 8.7 (m, 2 H), 9.0 (m, 2 H);
MS m/e 418 (MH+).
N-For m am idin o-3-(4-piper idin epr opion yl)-(R)-(-)-n ipe-
cotyl[(S)-3-a m in o-3-(3-p yr id yl)]p r op ion ic Acid (54). A
solution of 53 (1.0 g, 2.3 mmol) in EtOH (20 mL) and MeOH
(1 mL) at room temperature was treated with ethyl formi-
midate‚HCl (0.40 g, 1.6 mol equiv), stirred for 7 h, treated with
Et2O (15 mL), and refrigerated for 4 days to afford crystals.
The crystals were filtered and dried, and then dissolved in 4
N HCl (15 mL). This solution was stirred for 28 h and
evaporated. The resultant foam was dissolved in MeCN/water
(9:1), cooled in an ice bath, and filtered to afford 54 as a white
N-3-(4-P ip er id in ep r op -2-en oyl)p yr r olid in e-3-ca r b on -
yl[(S)-3-a m in o-3-(3-p yr id yl)]p r op ion ic Acid (58). Com-
pound 58 was prepared as shown in Schemes 1 and 8. Racemic
methyl pyrrolidine-3-carboxylate was prepared by the method
of J . Saunders26 and then carried forward as described for 56.
Compound 58 was isolated as a white powder (0.43 g): mp
1
foam (0.56 g): mp 49-55 °C; H NMR (DMSO-d6) δ 1.2-1.9
(m, 11 H), 2.3 (m, 3 H), 2.5 (m, 1 H), 2.8 (m, 5 H), 3.2 (d, J )
8 Hz, 2 H), 3.8 (m, 2 H), 4.2 (m, 2 H), 5.3 (m, 1 H), 7.9 (t, J )
4 Hz, 1 H), 8.6 (m, 1 H), 8.7 (m, 1 H), 9.0 (m, 2 H), 9.32 (s, 1
H); MS m/e 444 (MH+); UV (MeOH) λmax 261 nm.
1
118-122 °C; H NMR (DMSO-d6) δ 1.4-1.9 (m, 8 H), 2.3 (m,
1 H), 2.5 (m, 1 H), 2.8 (m, 5 H), 3.2 (d, J ) 8 Hz, 2 H), 3.8 (m,
2 H), 4.2 (m, 2 H), 5.3 (m, 1 H), 6.2 (d, 1 H) 6.6 (m, 1 H), 8.0
(t, J ) 4 Hz, 1 H), 8.6 (d, J ) 5 Hz, 1 H), 8.8 (d, J ) 4 Hz, 1
H), 9.1 (m, 3 H); MS m/e 401 (MH+).
2-Cycloh exylet h yl N-3-(4-p ip er id in ep r op ion yl)-(R)-
(-)-n ip ecotyl[(S)-3-a m in o-3-(3-p yr id yl)]p r op ion a te (55).
Compound 53 was prepared as shown in Scheme 1. A mixture
of N-Boc-3-(4-piperidinepropionyl)-(R)-(-)-nipecotyl-[(S)-3-
amino-3-(3-pyridyl)]propionic acid (0.60 g, 1.2 mmol, see 2) in
DCM (25 mL), 2-cyclohexylethyl alcohol (0.48 mL, 3 mol equiv),
and NMM (0.25 mL, 3 mol equiv) at 23 °C was treated with
N-[(4,4′-Bip ip er id in -1-yl)ca r b on yl]-(R)-(-)-n ip ecot yl-
[(S)-3-a m in o-3-(3-p yr id yl)]p r op ion ic Acid (59). Intermedi-
ate 7 (2.0 g, 5.5 mmol) was dissolved in DCM (140 mL), cooled
(5 °C), treated with 4-nitrophenylchloroformate (1.1 g, 1 mol

5264 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Hoekstra et al.
Syndrome. Circulation 1998, 97, 340-349. (b) Weller, T.; Alig,
L.; Beresini, M.; Blackburn, B.; Bunting, S.; Hadvary, P.;
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equiv) and NMM (2.0 mL, 3 mol equiv), and stirred for 2 h.
The mixture was diluted with water (15 mL), the layers were
separated, and the organic layer was dried (Na2SO4) and
evaporated to an oil. The oil was dissolved in MeCN (70 mL),
treated with N-Boc-4,4′-bipiperidine (1.3 g, 1.5 mol equiv) and
DMAP (0.40 g, 1 mol equiv), and heated at reflux for 24 h.
The mixture was cooled, evaporated to a solid, and partitioned
between EtOAc (150 mL) and 1 N NaOH (20 mL). The layers
were separated, and the organic layer was dried (Na2SO4),
evaporated to a solid, and purified by silica gel chromatography
(8% EtOH/DCM) to give methyl N-Boc-[(4,4′-bipiperidin-1-
yl-)carbonyl]-(R)-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)]propionate
as a green glass (0.90 g, 47%). The glass was saponified and
deprotected as described previously (see 2) to give 59 as a pale
yellow powder (0.73 g): mp 121-125 °C; 1H NMR (DMSO-d6)
δ 1.0 (m, 2 H), 1.1-1.4 (m, 6 H), 1.6 (m, 3 H), 1.8 (m, 4 H), 2.2
(m, 2 H), 2.7 (m, 6 H), 3.2 (d, J ) 6 Hz, 4 H), 3.5 (m, 1 H), 3.7
(m, 2 H), 4.1 (m, 1 H), 5.2 (m, 1 H), 7.9 (t, J ) 5 Hz, 1 H), 8.3
(d, J ) 5 Hz, 1 H), 8.8 (m, 5 H); MS m/e 472 (MH+); UV (MeOH)
λmax 261 nm.
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