Fibrinogen receptor (GPIIb-IIIa) antagonists derived from 5,6-bicyclic templates. Amidinoindoles, amidinoindazoles, and amidinobenzofurans containing the N-α-sulfonamide carboxylic acid function as potent platelet aggregation inhibitors

Article abstract of DOI:10.1021/jm9704863

A series of highly potent and specific fibrinogen receptor antagonists have been discovered and optimized through structural modification of the novel amidinoindole and benzofuran compounds, I and II. Systematic linker optimization afforded the amidinoben

Full text of DOI:10.1021/jm9704863

4308
J . Med. Chem. 1997, 40, 4308-4318
F ibr in ogen Recep tor (GP IIb-IIIa ) An ta gon ists Der ived fr om 5,6-Bicyclic
Tem p la tes. Am id in oin d oles, Am id in oin d a zoles, a n d Am id in oben zofu r a n s
Con ta in in g th e N-r-Su lfon a m id e Ca r boxylic Acid F u n ction a s P oten t P la telet
Aggr ega tion In h ibitor s
Ting Su,*,† Mary Ann H. Naughton,† Mark S. Smyth,† J ack W. Rose,† Ann E. Arfsten,† J efferson R. McCowan,‡
J oseph A. J akubowski,‡ Virginia L. Wyss,‡ Kenneth J . Ruterbories,‡ Daniel J . Sall,‡ and
Robert M. Scarborough*,†
COR Therapeutics, Inc., 256 East Grand Avenue, South San Francisco, California 94080, and Lilly Research Laboratories,
Eli Lilly and Company, Indianapolis, Indiana 46285
Received J uly 28, 1997X
A series of highly potent and specific fibrinogen receptor antagonists have been discovered
and optimized through structural modification of the novel amidinoindole and benzofuran
compounds, I and II. Systematic linker optimization afforded the amidinobenzofuran-
containing inhibitor 29, which displayed an IC50 value of 250 nM in platelet aggregation assays.
Attempts to enhance activity by modification of the â-position of the â-alanyl carboxylate group
of 29 had only a modest effect on inhibitory activity in aggregation assays. Analogues prepared
to enhance the activity by conformational restriction were also found to be equally or less potent.
In contrast, modification at the R-position of the â-alanyl carboxylate group resulted in the
identification of extremely potent and novel amidinobenzofuran-containing derivatives 46-
49. Reexamination of 5,6-bicyclic aromatic nucleus led to the further identification of
amidinoindole- and amidinoindazole-containing derivatives 53-55. These analogues, 46-49
and 53-55, exhibited potent in vitro activity with IC50 values of 25-65 nM in platelet
aggregation assays and an IC50 value of 2 nM in fibrinogen binding assays and demonstrated
a selectivity of >50000-fold for GPIIb-IIIa versus the most closely related integrin, the
vitronectin receptor, Rvâ3.
In tr od u ction
Adhesion of platelets to damaged blood vessel walls
or following rupture of atherosclerotic plaque initiates
a series of biochemical and cellular activations that
promote platelet aggregation and fibrin formation and
ultimately thrombus formation, critical events in arte-
rial thrombosis.1,2 Fibrinogen (Fg) and other adhesive
proteins bind to an activated membrane-bound glyco-
protein (GP) complex, GPIIb-IIIa, found on platelets
mediating the final common pathway leading to platelet
aggregation.3-5 Because of the pivotal role that platelet
GPIIb-IIIa plays in thrombosis, antagonists which
compete for adhesive protein binding to GPIIb-IIIa are
novel antithrombotic agents for the treatment of severe
arterial thrombotic conditions such as unstable angina,
myocardial infarction, and stroke. With the discovery
F igu r e 1.
that peptides containing the arginylglycylaspartyl (RGD)
certain distance appended to an appropriate template
sequence are capable of effectively inhibiting the binding
has been a common theme in the strategy in the design
of fibrinogen and other adhesive ligands to GPIIb-IIIa,
of a variety of potent nonpeptide GPIIb-IIIa antagonists.
considerable synthetic effort toward the development of
Utilizing 5-amidinoindole as an arginine isostere and
RGD-based peptide and nonpeptide GPIIb-IIIa antago-
appending acidic tails of varying lengths in an effort to
mimic the critical distance between the guanidyl and
nists has ensued.6-16
Previous structure-activity studies of peptide and
nonpeptide antagonists of GPIIb-IIIa have identified
structural features of these inhibitors that contribute
carboxyl binding sites within the RGD sequence, Mc-
Cowan et al.17 have identified the amidinoindole acid I
and amidinobenzofuran acid II as moderately potent
to specific GPIIb-IIIa reactivity: a basic functional
RGD nonpeptide mimics (Figure 1). We now present
group such as an amino, guanidino, or benzamidino
further efforts undertaken to enhance the activity of this
appropriately oriented with respect to the other impor-
novel series of amidinoindole- and amidinobenzofuran-
tant functional group, which is optimally a carboxylic
containing derivatives I and II and to identify leads for
potential development as orally available GPIIb-IIIa
acid. Placing the basic and acidic functionalities at a
antagonists. As part of this study we have examined
compounds of the general structure III where system-
atic linker optimization, conformational restriction, and
† COR Therapeutics.
‡ Lilly Research Laboratories.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
S0022-2623(97)00486-X CCC: $14.00 © 1997 American Chemical Society

GPIIb-IIIa Antagonists Derived from 5,6-Bicyclic Templates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4309
Sch em e 1a
a
(a) EtOH, HCl; (b) EtOH, NH3; (c) Cbz-OSu, TEA, DMF; (d) LiOH, THF/H2O.
Sch em e 2a
a
(a) H2S, Et3N, pyridine; (b) MeI, acetone; (c) NH4OAc, MeOH; (d) Cbz-OSu, TEA, DMF; (e) LiOH, THF/H2O.
Sch em e 3a
Sch em e 5a
a
(a) H2S, Et3N, pyridine; (b) MeI, acetone; (c) NH4OAc, MeOH;
(d) DIEA, TMS-Cl; then DIEA, Cbz-Cl.
Sch em e 4a
a
(a) NaNO2, H2O, HCl; (b) NaClO2, NaH2PO4; (c) H2S, Et3N,
pyridine; (d) MeI, acetone; (e) NH4OAc, MeOH; (f) DIEA, TMS-
Cl; then DIEA, Cbz-Cl.
a
(a) Hydroxymethyl resin, BOP, DMAP, DMF; (b) (1) TFA, (2)
DIEA; (c) Boc-N-linker-CO2H, DCC, HOBt; (d) (1) TFA, (2) DIEA;
(e) 4 or 7, DCC, HOBt; (f) HF.
modification at both the R- and â-positions to the
carboxylate group have been made. Following optimi-
zation of the general structure III, we reexamined the
aromatic nucleus through preparation of compounds of
the general structure IV (Figure 1). Several additional
analogues with potencies comparable to those derived
from general structure III were identified. This report
describes the design, synthesis and identification of a
number of GPIIb-IIIa antagonists which exhibit potent
activity as platelet aggregation inhibitors as well as
marked selectivity for the fibrinogen receptor, GPIIb-
IIIa, versus the vitronectin receptor, Rvâ3, the most
closely related integrin.
absolute ethanol afforded the amidinoindole ethyl ester
3 in quantitative yield. Protection of the amidino
functionality and subsequent hydrolysis of the ethyl
ester gave key intermediate 4, which is suitably pro-
tected for both solid-phase and solution chemistries.
After unsuccessful attempts to synthesize 5-amidi-
nobenzofuran-2-carboxylic acid ester 6 employing an
approach similar to that depicted in Scheme 1, an
alternative known three-step protocol18 was used for the
conversion of the cyano group to the amidino group. This
consisted of sequential reaction of nitrile 517 with
hydrogen sulfide, methyl iodide, and ammonium acetate
(Scheme 2). The amidino function of the resulting
5-amidinobenzofuran-2-carboxylic acid ester 6 was pro-
tected, and the ester was hydrolyzed to give the key
intermediate 7.
The methods utilized in the preparation of the ter-
minal carboxylic acid motifs 8a -k used in the syntheses
of Scheme 5 are described in the literature and are
referenced as noted in Table 1. A variety of racemic
â-aryl â-amino acids 8a -e were prepared from the
appropriate aryl aldehyde, malonic acid, and ammonium
acetate via a modified Knoevenagel procedure and
protected as Boc derivatives.19 The racemic ethynyl
â-amino acid 8f was prepared according to a literature
procedure described by Metcalf.20 The racemic 3-[(tert-
butoxycarbonyl)amino]-5-(3-indolyl)valeric acid 8g was
Ch em istr y
Novel amidinoindole, amidinobenzofuran, and ami-
dinoindazole-containing inhibitors 18-55 were synthe-
sized using both solution-phase and solid-phase peptide
synthesis following the synthetic sequence shown in
Scheme 5. The synthesis of various components utilized
in these syntheses was accomplished as depicted in
Schemes 1-4 and as referenced in Table 1.
The preparation of the key protected segment, 5-Cbz-
amidinoindole-2-carboxylic acid 4, is outlined in Scheme
1. The imidate salt 2 was synthesized using Pinner
conditions by passing dry hydrogen chloride into a
solution of nitrile 1 in absolute ethanol at 25 °C.17
Reaction of the crude imidate salt 2 with ammonia in

4310 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Ta ble 1. Methods for Preparation of Compounds 8a -k
Su et al.
Resu lts a n d Discu ssion
Bioa ssa ys. Three biological assays were used to
assess the in vitro activity of the compounds described
in this study: (i) inhibition of platelet aggregation
induced by 20 µM adenosine 5′-diphosphate (ADP) in
human platelet rich plasma (h-PRP), (ii) inhibition of
fibrinogen binding to purified immobilized GPIIb-IIIa
(integrin, RIIbâ3), and (iii) inhibition of vitronectin bind-
ing to the purified immobilized vitronectin receptor Rvâ3
in order to determine the integrin selectivity of the
compounds.6,7 All data are given in Tables 2-7.
On the basis of our previous observation17 as well as
those reported in the literature for other series of
integrin inhibitors, we initially targeted three regions
of the lead molecule III for modification: the linker unit,
the â-position of the carboxylate terminus, and the
R-position of the carboxylate terminus. The â-phenyl-
â-alanine carboxylate subunit was initially incorporated
into all analogues due to the availability of the requisite
starting materials and the intention to incorporate a
hydrophobic group at the â-position of the carboxylate
function which has been demonstrated by Scarborough
et al.,25a Zablocki et al.,26 and others25b to be beneficial
for the potency in different series of GPIIb-IIIa inhibi-
tors. We then reexamined the 5,6-bicyclic nucleus while
incorporating the optimized spacer and carboxylate
modifications as determined from general structure III.
1. Lin k er Mod ifica tion s. Our synthetic modifica-
tion of III focused initially on optimizing the linkage
between the amidino and carboxylate functionalities
using the following approaches:
(a ) In tr od u ction of N-r-a n d C-r-Meth yl Gr ou p s
a s Con for m a tion a l Con str a in ts w ith in a Va r iety
of Am in o Acid Lin k er s. It is known that substituting
methyl groups for hydrogen atoms in the backbones of
peptides decreases their available conformational space.14
We employed this conformational restriction approach
on lead compound I (Table 2). As a starting point for
reference, the initial compound prepared contained a
glycine linker (compound 18) which displayed only
modest GPIIb-IIIa inhibitory activity (IC50 ) 50 µM in
PRP and IC50 ) 10 µM in the GPIIb-IIIa ELISA, Table
2). Replacement of the glycyl linker with the N-
methylated glycine residue afforded 19 and led to a
slight enhancement in the in vitro potency of approxi-
mately 2-fold increase in PRP assay versus 18 and no
enhancement in the ELISA assay. However, the more
sterically demanding C-R-dimethylated glycine analogue
20 had diminished inhibitory potency (5-10 times less
active in PRP and ELISA assays) relative to 18.
Replacement of the glycyl linker with a â-alanyl linkage
to afford analogue 21 enhanced the activity of 18 by
approximately 6-fold in the PRP assay and 10-fold in
the ELISA assay. N-R- and C-â-methylation of the
â-alanine analog 21 afforded compounds 22 and 23,
which were comparable to the unsubstituted â-alanine
derivative 21 in activity in platelet aggregation. Inter-
estingly, the N-methyl analogue 22 was significantly
more potent in the purified ligand binding assay,
suggesting that the intrinsic activity against the recep-
tor was enhanced by this modification but did not
translate into a corresponding enhancement of activity
in the aggregation assay. This may be due to increased
plasma protein binding of this analogue in the PRP
assay as has been noted in other GPIIb-IIIa inhibitors.17
A C-â-trifluoromethyl-containing compound 24 dis-
synthesized following the procedure described by Dug-
gan et al.21 General methods as described by Egbertson
and co-workers22 were used to prepare R-substituted
amino acid derivatives 8h -k .
Compounds 10 and 13 (Scheme 3) were prepared from
the corresponding nitriles, 9 and 12,17 using the same
three-step process described in Scheme 2. Although all
attempts to protect the amidino groups of 10 and 13
using Cbz-OSu failed, an alternate procedure utilizing
in situ N-silylation of amidino acids 10 or 13 with DIEA
and TMS-Cl in refluxing CH2Cl2 followed by addition
of DIEA and then Cbz-Cl afforded 11 and 14 (50% as
the bis-Cbz-protected derivative), respectively.23
Indazole acid 17 (Scheme 4) was prepared from
6-cyanoindole17 by a two-stage rearrangement-oxida-
tion procedure affording 15. Conversion of the nitrile
functionality to the bis-Cbz-protected amidino moiety
as described in Scheme 3 afforded the protected indazole
acid 17.
The â- and R-substituted â-amino acids 8a -k were
attached through the carboxylate functionality to (hy-
droxymethyl)polystyrene resin using the coupling agent
BOP (Scheme 5). Compounds 18-49 were readily
assembled using standard solid-phase peptide synthesis
protocols (DCC-HOBt) using an Applied Biosystems
431A peptide synthesizer. Compounds 50-55 were also
readily synthesized using essentially the same approach
as in Scheme 5 except that manual solid-phase peptide
synthesis techniques were utilized in lieu of the auto-
mated system.

GPIIb-IIIa Antagonists Derived from 5,6-Bicyclic Templates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4311
Ta ble 3. Linker Modification of Lead Compound II
Ta ble 2. Linker Modification of Lead Compound I
1. Concentration required to reduce ADP (20 µM) induced
human platelet aggregation response by 50% for the PRP assay.
A minimum of two determinations were made for each compound.
2. Concentration required to reduce binding of fibrinogen to
purified GPIIb-IIIa by 50% or the concentration required to reduce
binding of vitronectin to purified Rvâ3 by 50%. A minimum of two
determinations were made for each compound. The average error
for the assay was (15%. 3. Not Determined.
residues were replaced by several rigid cyclic linkers.
These modifications which included the incorporation
of the 3-piperidine carboxyl, prolyl, and tetrahydroiso-
quinoline-3-carboxyl linkers resulted in equally potent
analogues (33 and 35 related to 28, 32 related to 29;
see Table 3) in the amidinobenzofuran series. While
only a limited number of substitutions were studied,
they were generally tolerated. However, conformational
restriction introduced by these substitutions did not
necessarily enhance the activity within this series. The
25-fold difference in activity observed for 33 versus 34
suggests a receptor preference for the S-configuration
at the R-position of the rigid linker proline.
For both series of compounds, insertion of a simple
â-alanyl linker produced compounds 21 and 29 with
enhanced activity of approximately 10-fold in PRP
assays and 2-fold in the ELISA assay relative to the
corresponding glycine-containing analogues 18 and 28.
This result reemphasizes the importance of the distance
between the amidino and carboxylic acid.
played lower potency than the â-methyl-containing
compound 23, which may be due to electronic rather
than steric factors.
In the corresponding amidinobenzofuran-containing
series, the reference glycyl-containing inhibitor 28 was
enhanced to the same degree by replacement with the
â-alanine linker, compound 29, which was 30-fold more
potent than amidinoindole-containing compound 21 in
the aggregation assay and 6-fold more potent in the
ligand binding assay (Table 3). Attempts to introduce
conformational restrictions through N-R-and C-â-me-
thylation of the â-alanine linker (30, 31) again did not
enhance the activity over 29 in the aggregation assay.
In this series of analogues, the â-methyl-â-alanyl-
containing compound displayed a 5-7-fold enhancement
in the ELISA assay compared to 29, but a similar
enhancement in the PRP assay was not observed.
However, since the goal of this effort was to prepare
analogues which displayed superior activity in plasma,
where these agents must exert their activity in vivo, the
relative activities of analogues in PRP is important and
guided our efforts.
On the basis of the in vitro potency and synthetic
accessibility, the amidinobenzofuran 29, which con-
tained the unsubstituted â-alanyl linker, was chosen as
a lead for further structural optimization directed at the
R- and â-positions of the carboxylic acid terminus.
2. Mod ifica tion a t th e â-P osition of th e Ca r -
boxyla te Ter m in u s. Numerous studies of GPIIb-IIIa
inhibitors have suggested that residues at or very near
the aspartic acid of the RGD sequence modulate the
selectivity of ligand binding to integrins, and introduc-
tion of aromatic or other hydrophobic residues proximal
to the RGD site can significantly enhance the inhibitory
(b) Rep la cem en t of Glycin e a n d â-Ala n in e by
Mor e Rigid Lin k er s. To determine whether the
additional or alternate conformational restriction within
the linker would modulate activity, glycine or â-alanine

4312 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Su et al.
F igu r e 3.
Ta ble 5. Effects of R-Substitution on Platelet Aggregation and
Adhesive Protein Binding to Purified Integrins
F igu r e 2.
Ta ble 4. Effects of â-Substitution on Platelet Aggregation and
Adhesive Protein Binding to Purified Integrins
analogues displayed IC50 values of 0.2-0.6 µM for
inhibition of ADP-mediated platelet aggregation. Less
than a 3-fold difference in platelet aggregation inhibition
and fibrinogen binding inhibition in the ELISA assay
was observed between the most and least potent inhibi-
tors in this series of phenyl-substituted analogues. The
overall similar potency of compounds 37-44 suggests
that the moiety at the position â to the carboxylic acid
terminus interacts with a region of GPIIb-IIIa that is
capable of accepting a fairly broad range of hydropho-
bicities, electronegativities, and molecular volumes. The
compounds in this series also did not have any ap-
preciable activity with the vitronectin receptor, Rvâ3.
These observations, coupled with our goal to increase
the activity at least 10-fold relative to analogue 29,
prompted us to further investigate the effects of R-sub-
stitution in the interaction of these analogues with
GPIIb-IIIa.
activity and specificity of the RGD analogues.25 On the
basis of an extensive SAR study at a position â to the
carboxylic acid terminus in a different series of GPIIb-
IIIa inhibitors, Zablocki et al.26 have recently reported
the potent platelet aggregation inhibitor V (Figure 2).
In our series, we have utilized a similar approach to
study the effect of â-substitutions to the carboxylic acid
on the interaction of amidinobenzofuran-containing
analogues with GPIIb-IIIa.
A series of analogues related to 3-phenyl-â-alanine
derivative 29 were prepared (analogues 36-44; Table
4). When the â-phenyl group was replaced by other
nonaromatic residues such as H, CF3, or alkynyl, these
analogues (36-38) were not significantly different in
potency from the phenyl containing analogue 29 in the
aggregation assay, but had moderate (∼4-fold) increase
in activity in the ELISA assay. While it was anticipated
that increasing the electron-withdrawing or -donating
ability of the ring system would modulate the inhibitory
activity of the analogues, varying the phenyl ring
substituent had only modest effects on analogue activity
as shown in Table 4 in both the PRP and ELISA assays.
These â-substituted amidinobenzofuran-containing acid
3. Mod ifica tion a t th e r-P osition of th e Ca r -
boxyla te Ter m in u s. Egbertson et al.22 and Hartman
et al.11 have reported that in a different series of
tyrosine-containing GPIIb-IIIa inhibitors introduction
of sulfonyl substituents on the R-amino group of com-
pound VI (Figure 3) resulted in a class of very potent
and specific inhibitors of GPIIb-IIIa. This modification
has also been applied to other series27 but is not
uniformly successful in enhancing the GPIIb-IIIa in-
hibitory activity of compounds.28 In our series, the free
R-amino-containing analogue 45 was nearly equipotent
to the unsubstituted analogue 36. Incorporation of the
butanesulfonamido functionality into the carboxylic acid
terminus afforded analogue 46 which displayed a 6-fold
enhancement in activity in the platelet aggregation
assay and approximately 20-fold enhancement in the
ligand binding assay (IC50 ) 2.0 nM) relative to 45
(Table 5). Similarly, several R-arylsulfonamide-substi-
tuted amidinobenzofuran-containing acids (47-49) were
prepared which were found to be nearly equivalent to
butanesulfonamide 46.

GPIIb-IIIa Antagonists Derived from 5,6-Bicyclic Templates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4313
Ta ble 6. Effects of Aromatic Amidine Nucleus Modification
Ta ble 7. Effects of Aromatic Amidine Nucleus Modifications in
the Sulfonamide Series
the 5-membered ring of the 5,6-bicyclic nucleus modu-
lates the potency in this series. For example, benzofu-
ran-containing compound 29 is 30-fold more potent in
the PRP assay and 6-fold more potent in the ELISA
assay than the corresponding indole-containing com-
pound 21. The main difference between these two
compounds is the presence of the oxygen in 29 which is
a better H-bond acceptor than is the N-H in compound
21. Likewise, indazole-containing compound 52 is 3-fold
better in the platelet aggregation assay than is the
corresponding indole-containing compound 51 with the
main difference being the presence of the second nitro-
gen in 52, which also may be acting as an H-bond
acceptor. An alternate explanation for these observed
differences may be that the basicity of the amidino
group has been affected, thereby altering the potency
of the compounds. Our data cannot distinguish between
these or other possible explanations for the activities
in this series.
4. Mod ifica tion of th e 5,6-Bicyclic Nu cleu s.
Having identified compound 29 as an early lead, we
were interested in briefly reexamining the 5,6-bicyclic
nucleus to determine whether additional modifications
in this region of the molecules could further enhance
potency. As such, compounds 50-52 were prepared and
evaluated relative to compounds 21 and 29 (see Table
6). While these modifications resulted in 3-13-fold
improved potency in the platelet aggregation assay
relative to indole-containing 21 (IC50 ) 8 µM), they did
not display enhanced activity over benzofuran-contain-
ing 29 (IC50 ) 0.25 µM). The relative potencies of 50,
51, and 52 versus 29 were, however, generally consis-
tent with the pattern previously observed17 for the same
aromatic nuclei in a different series of inhibitors.
Namely, the 2,6-substituted indole-containing com-
pound 50 and the 3,6-substituted indole-containing
compound 51 were approximately 5-9-fold weaker
inhibitors of platelet aggregation than benzofuran-
containing compound 29 while the 3,6-substituted in-
dazole-containing compound 52 was more potent than
either 50 or 51. Although in the previously reported
series of inhibitors17 the indazole-containing compound
was found to be more potent than the corresponding
benzofuran-containing compound, in this series inda-
zole-containing 52 was 2.5-fold weaker than benzofuran-
containing 29.
Even though these modifications resulted in a 2.5-
10-fold loss in potency relative to compound 29, the
same aromatic nuclei were substituted into the R-sul-
fonamido series in order to study the potency-enhancing
effect of this functionality in conjunction with slightly
less than optimal aromatic nuclei (Table 7). Indeed,
compounds 53-55 demonstrated a 10-40-fold increase
in potency in the PRP assay over compounds 50-52.
They were also found to be equivalent to compounds
46-49 in both the PRP and binding assays, as well as
in integrin selectivity.
As shown in Tables 5 and 7, analogues 46-49 and
53-55 were by far the most potent analogues prepared
in this study. This result suggests that a hydrophobic
sulfonamide at the R-position enhances the binding of
this class of compounds to GPIIb-IIIa. These observa-
tions are consistent with the results published by
Hartman et al.11 and Egbertson et al.22 who have
proposed that the R-sulfonamide substituents may be
interacting with an unexploited “exosite” contained
within the GPIIb-IIIa complex. The observation that
modifications of the phenyl ring in the â-position of 29
resulting in compounds 39-44 did not have significant
effects on potency might be due to the fact that these
various â-substituents could be interacting with this
exosite. A similar lack of variability in potencies is
present for analogues 46-49 and 53-55, all of which
contain an R-sulfonamide functionality. A comparison
of the PRP data for compounds 29, 51, and 52 (about a
10-fold range) relative to 46, 54, and 55 (less than 2-fold
in PRP and ELISA assays) demonstrates that the
incorporation of an R-sulfonamide into an inhibitor in
this series can override other potency modulating
characteristics of the molecule such as the presence of
an H-bond acceptor in the 5,6-bicyclic nucleus. The fact
that several different aromatic rings in the sulfonamide
While the modifications to the 5,6-bicyclic nucleus did
not result in compounds which were more potent
analogues than 29 or 46, the data did suggest that the
potential presence or absence of an H-bond acceptor in

4314 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Su et al.
antagonists 46-49 and 53-55 (IC50 ) 0.025-0.065 µM
in aggregation assays). The integrin specificity in this
series may, in part, be attributed to the presence of an
aryl amidino which serves as the base which replaces
the arginine guanidine in RGD sequences as has been
previously observed.8,11 The 10-fold to 40-fold potency
enhancement of analogues 46-49 and 53-55 compared
to their corresponding â-substituted analogues 37-44
and 50-52 is likely due to their interaction with a
previously postulated “exosite” on GPIIb-IIIa by the
sulfonamide functionality.
Exp er im en ta l Section
1H NMR spectra were recorded on a Varian Unity + 400
spectrometer unless otherwise noted. Low-resolution mass
spectra were recorded with a Vestec 201XL analytical spec-
trometer performed at SRI International, with an ABI Bio-
Ion 20 mass spectrometer performed at Chiron Mimotopes
Peptide Systems or with a Perkin-Elmer SCIEX API-I per-
formed at Synpep Corp. High-resolution mass spectra were
recorded with a VG ZAB2-EQ high-resolution mass spectrom-
eter and performed at the University of California at Berkeley.
Normal-phase silica gel (EM Science, silica gel 60) was used
for chromatography. Final compounds were purified by re-
verse phase HPLC using a Waters 4000Prep, Waters 490E
multiwavelength detector, and Vydac 218TP1022 column (10
µm, C18, 22 × 250 mm). Purity of the compounds were
confirmed by two diverse HPLC systems using Waters 600
controller, Waters 996 photodiode array detector and Vydac
201HS54 column (5 µm, C18, 4.6 × 250 mm).
5-(Cbz-Am id in o)in d ole-2-ca r boxylic Acid (4). (a ) Eth yl
5-Am id in oin d ole-2-ca r boxyla te (3). A slurry of 5-cyanoin-
dole-2-carboxylic acid (1) (7 g, 37.6 mmol) in 800 mL of EtOH
was treated with a stream of HCl gas for 2 h. The resulting
solution was capped, stirred at room temperature for 64 h, and
evaporated in vacuo to afford 2. The residue was reconstituted
in EtOH, and the mixture was treated with a stream of NH3
gas for 1 h. The reaction mixture was stirred at room
temperature overnight and was concentrated to afford 3 as a
solid (10.72 g): 1H NMR (CD3OD) δ 9.12 (b, 1H), 8.56 (b, 1H),
8.22 (s, 1H), 7.64 (m, 2H), 7.32 (s, 1H), 4.4 (q, J ) 7 Hz, 2H),
1.4 (t, J ) 7 Hz, 3H); exact mass (FAB, M + 1)+ calcd 232.1086,
found 232.1089.
(b) Eth yl 5-(Cbz-a m id in o)in d ole-2-ca r boxyla te. A mix-
ture of ethyl 5-amidinoindole-2-carboxylate (3) (3.27 g, 12.2
mmol), N-(benzyloxycarbonyloxy)succinimide (3.04 g, 12.2
mmol), and triethylamine (3.4 mL, 24.4 mmol) in DMF (150
mL) was stirred at room temperature overnight. The mixture
was diluted with ethyl acetate, and the organic layer was
washed with water three times, dried (anhydrous Na2SO4),
filtered, and evaporated to yield the title compound as a white
solid (4.52 g, 100%): 1H NMR (CD3OD) δ 8.25 (m, 1H), 7.64
(m, 2H), 7.49-7.34 (m, 6H), 5.39 (s, 2H), 4.4 (q, J ) 7 Hz, 2H),
1.4 (t, J ) 7 Hz, 3H); exact mass (FAB, M + 1)+ calcd 366.1454,
found 366.1445.
F igu r e 4. Plasma concentration of active species after oral
administration of 56, 57, or 58.
moieties in compounds 47-49 were well tolerated
suggests that modifications in this portion of the
molecules may allow for modulation of oral absorption
profiles, while retaining potent GPIIb-IIIa activity.
Prodrugs of the more potent analogues (30 and 46)
were prepared using standard peptide-coupling proce-
dures. The ethyl ester of analogue 46 was obtained as
its single ethyl ester prodrug, analogue 56.29 Addition-
ally the N-[(acyloxy)methoxy]carbonyl group30a,b or the
carbobenzyloxy group was added to the amidine function
of the ethyl ester of analogue 30 to afford the double
prodrugs 57 and 58, respectively.29 The single prodrug
56 and the double prodrugs 57 and 58 were evaluated
in vivo in rats following oral administration at a dose
of 10 mg/kg. Determination of the plasma levels
achieved over time of the parent carboxylic acids 30 and
46 were consistently low and suggest poor oral bioavail-
ability of these inhibitors (Figure 4). While many of the
analogues in this series display potent in vitro activity,
their potential as leads in the identification of orally
available inhibitors was not realized.
(c) 5-(Cbz-Am id in o)in d ole-2-ca r boxylic Acid (4).
A
solution of ethyl 5-(Cbz-amidino)indole-2-carboxylate (4.4 g,
12 mmol) in THF (25 mL) was treated with LiOH (1.5 g, 36
mmol) and H2O (25 mL). The mixture was stirred at room
temperature overnight. The organic solvent was evaporated
in vacuo. The aqueous layer was extracted with EtOAc and
acidified to pH 3-4 with 2 N aqueous HCl at 0 °C. The
resulting solid was filtered and dried to give the corresponding
acid 4 as a white solid (3.77 g, 93.3%): 1H NMR (CD3OD) δ
8.24 (m, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.39 (m, 3H), 7.33
(bs, 1H), 5.38 (s, 2H); exact mass (FAB, M + 1)+ calcd 338.1141,
found 338.1139.
5-(Cbz-Am id in o)ben zofu r a n -2-ca r boxylic Acid (7). (a )
Meth yl 5-Am id in oben zofu r a n -2-ca r boxyla te (6). A solu-
tion of methyl 5-cyanobenzofuran-2-carboxylate (5) (4.48 g,
22.3 mmol) in pyridine/TEA, 5:1 (200 mL), was saturated with
H2S and stirred at room temperature until no starting material
could be detected by TLC. Excess H2S was extruded by a
gentle stream of nitrogen, and the solvents were removed to
give the corresponding thioamide (5.3 g, 99%) as a yellow solid.
Con clu sion s
In summary, we have reported the discovery and
optimization of a class of amidinoindole-, amidinoinda-
zole-, and amidinobenzofuran-containing acid com-
pounds which function as potent GPIIb-IIIa antagonists
and which are also effective inhibitors of platelet ag-
gregation. Structural optimization of the lead com-
pounds I, II, and III at the linker unit, at the â- and
R-positions of the carboxylate function, and at the
aromatic nucleus has provided very potent and specific

GPIIb-IIIa Antagonists Derived from 5,6-Bicyclic Templates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4315
A solution of the thioamide (5.3 g, 22.3 mmol) and iodomethane
(14 mL, 223 mmol) in acetone (250 mL) was heated to reflux
until no starting material could be detected by TLC. Complete
removal of the solvents yielded the corresponding thioiminom-
ethyl ester as a yellow salt. This material and ammonium
acetate (6.86 g, 89 mmol) in methanol (180 mL) was heated to
reflux for 1 h. The mixture was evaporated in vacuo, and the
resulting oil was triturated with THF to give a solid which
was collected by filtration, washed (THF), and dried to give
the title compound 6 (5.24 g, 100%): 1H NMR (CD3OD) δ 8.25
(s, 1H), 7.86 (m, 2H), 7.75 (s, 1H), 3.96 (s, 3H); exact mass
(FAB, M + 1)+ calcd 219.0770, found 219.0766.
(b) 5-(Cbz-Am id in o)ben zofu r a n -2-ca r boxylic Acid (7).
Compound 7 was synthesized by the same method for 4 using
6 in place of 3: 1H NMR (CD3OD) δ 8.24 (m, 1H), 7.83 (m,
2H), 7.64 (s, 1H), 7.48 (m, 2H), 7.393 (m, 3H), 5.39 (s, 2H);
MS (FAB) 339.0 (M + 1)+.
6-Am id in o-1H-in d a zole-3-ca r boxylic Acid (16). Com-
pound 16 was synthesized by the same method for 6 using 15
in place of 5: MS (DCI-NH3) 205 (M + 1)+.
6-(Bis-Cbz-am idin o)-1H-in dazole-3-car boxylic Acid (17).
Compound 17 was synthesized by the same method for 11
using 16 in place of 10: 1H NMR (CD3OD) δ 8.70 (d, J ) 1.0
Hz, 1H), 8.46 (d, J ) 8.79 Hz, 1H), 7.78 (dd, J ) 8.42, 1.47
Hz, 1H), 7.57 (d, J ) 6.59 Hz, 2H), 7.50 (d, J ) 6.23 Hz, 2H),
7.40 (m, 6H), 5.60 (s, 2H), 5.42 (s, 2H); MS (DCI-NH3) 473
(M + 1)+.
Gen er a l P r oced u r e for th e Atta ch m en t of Su bstitu ted
â-Am in o Acid s to Hyd r oxym eth yl Resin . Exa m p le 1. D,L-
3-(Boc-a m in o)-3-p h en ylp r op ion ic Acid Hyd r oxym eth yl
Resin . Hydroxymethyl resin (4 g, 0.749 mequiv of OH/g) was
suspended in DMF (40 mL). D,L-3-(Boc-amino)-3-phenylpro-
pionic acid (Aldrich) (3.18 g, 12 mmol), DMAP (0.37 g, 3 mmol),
DIEA (2.79 mL, 15 mmol), and BOP were added. The mixture
was rocked at room temperature overnight. The resulting
resin was collected in a fritted glass Buchner funnel, washed
with MeOH and DCM, and dried in vacuo.
3-[[2-(5-Am id in o-2-in d oleca r boxa m id o)a cetyl]a m in o]-
3-p h en ylp r op ion ic Acid (18). Compound 18 was synthe-
sized by standard automated solid-phase synthesis protocols
using an Applied Biosystems 431A peptide synthesizer (Foster
City, CA). D,L-3-(Boc-amino)-3-phenylpropionic acid hydroxym-
ethyl resin from example 1 described above was deprotected
with 50% TFA/DCM followed by coupling with N-Boc-glycine.
The Boc group was removed again with 50% TFA/DCM
followed by coupling with 5-(Cbz-amidino)indole-2-carboxylic
acid 4. Completed compound was released from the hy-
droxymethyl resin along with deprotection of the side chains
using standard hydrogen fluoride cleavage methods. It was
purified to homogeneity using reversed-phase high-perfor-
mance liquid chromatography: 1H NMR (CD3OD) δ 8.19 (s,
1H), 7.62 (s, 2H), 7.32 (m, 6H), 5.37 (m, 1H), 4.08 (s, 2H), 2.82
(m, 2H); exact mass (FAB, M + 1)+ calcd 408.1672, found
408.1661.
6-Am id in oin d ole-2-ca r boxylic Acid (10). Compound 10
was synthesized by the same method for 6 using 9 in place of
5: 1H NMR (CD3OD) δ 7.96 (t, J ) 0.7 Hz, 1H), 7.82 (d, J )
8.46 Hz, 1H), 7.43 (dd, J ) 8.46, 1.84 Hz, 1H), 7.11 (d, J ) 1.1
Hz, 1H); MS (DCI-NH3) 204 (M + 1)+.
6-(Cbz-a m id in o)in d ole-2-ca r boxylic Acid (11). To a
suspension of 6-amidinoindole-2-carboxylic acid (10) (1.15 g,
5.7 mmol) in anhydrous DCM (14 mL) at room temperature
under argon was added DIEA (6.0 mL, 34 mmol) followed by
slow addition of TMS-Cl (4.4 mL, 34 mmol). The resulting
solution was warmed to 40 °C, stirred for 1.5 h, and then cooled
to 0 °C. Another addition of DIEA (6.0 mL, 34 mmol) was
followed by Cbz-Cl (4.9 mL, 34 mmol). After the mixture was
stirred at 0 °C for 15 min and then at room temperature for
3 h, the reaction was quenched by the careful addition of 3 N
HCl (25 mL). The resulting suspension was cooled to 0 °C
and stirred vigorously for 15 min and filtered and the solid
rinsed with H2O and air-dried for 1 h. This solid was then
suspended in 50 mL of THF and mixed thoroughly, and DCM
(50 mL) was added. After being cooled to -78 °C, the solid
was filtered, rinsed with DCM (50 mL), and dried under high
vacuum to afford pure title compound 11 (1.271 g, 66%) as an
off-white powder: 1H NMR (CD3OD) δ 7.99 (t, J ) 1.1 Hz, 1H),
7.91 (dd, J ) 8.45, 1.1 Hz, 1H), 7.45 (m, 6H), 7.27 (d, J ) 1.47
Hz, 1H), 5.43 (s, 2H); MS (LC-MS) 338 (M + 1)+.
3-[[2-(N-Meth yl-5-am idin o-2-in dolecar boxam ido)acetyl]-
a m in o]-3-p h en ylp r op ion ic Acid (19). Compound 19 was
synthesized by the same method for 18 using N-Boc-N-
methylglycine in place of N-Boc-glycine: exact mass (FAB, M
+ 1)+ calcd 422.1828, found 422.1825.
6-Am id in oin d ole-3-ca r boxylic Acid (13). Compound 13
was synthesized by the same method for 6 using 12 in place
of 5: MS (DCI-NH3) 204 (M + 1)+.
6-(Cbz-a m id in o)in d ole-3-ca r boxylic Acid (14). Com-
pound 14 (as a mixture with 50% di-Cbz protected as deter-
mined by RP-HPLC) was synthesized by the same method for
11 using 13 in place of 10: MS (DCI-NH3) 338 and 472 (M +
H)+.
3-[[2-(N,N′-Dim eth yl-5-a m id in o-2-in d oleca r boxa m id o)-
a cetyl]a m in o]-3-p h en ylp r op ion ic Acid (20). Compound 20
was synthesized by the same method for 18 using N-Boc-2,2′-
dimethylglycine in place of N-Boc-glycine: 1H NMR (CD3OD)
δ 8.21 (s, 1H), 7.62 (s, 2H), 7.32 (m, 6H), 5.36 (m, 1H), 2.82
(m, 2H), 1.62 (s, 3H), 1.58 (s, 3H); exact mass (FAB, M + 1)+
calcd 436.1985, found 436.1985.
3-[[3-(5-Am id in o-2-in d oleca r boxa m id o)p r op ion yl]a m i-
n o]-3-p h en ylp r op ion ic Acid (21). Compound 21 was syn-
thesized by the same method for 18 using N-Boc-â-alanine in
place of N-Boc-glycine: 1H NMR (CD3OD) δ 8.19 (s, 1H), 7.62
(s, 2H), 7.20 (m, 6H), 5.37 (t, 1H), 3.60 (t, 2H), 2.78 (m, 2H),
2.58 (m, 2H); exact mass (FAB, M + 1)+ calcd 422.1828, found
422.1825.
3-[[3-(N-Meth yl-5-a m id in o-2-in d oleca r boxa m id o)p r o-
p ion yl]a m in o]-3-p h en ylp r op ion ic Acid (22). Compound
22 was synthesized by the same method for 18 using N-Boc-
N-methyl-â-alanine in place of N-Boc-glycine: 1H NMR (CD3-
OD) δ 8.19 (s, 1H), 7.62 (s, 2H), 7.21 (m, 6H), 5.37 (t, 1H),
3.83 (m, 2H), 3.29 (m, 3H), 2.78 (m, 2H), 2.62 (m, 2H); exact
mass (FAB, M + 1)+ calcd 436.1985, found 436.1977.
3-[[3-(5-Am id in o-2-in d oleca r b oxa m id o)-3-m et h ylp r o-
p ion yl]a m in o]-3-p h en ylp r op ion ic Acid (23). Compound
23 was synthesized by the same method for 18 using N-Boc-
R-methyl-â-alanine in place of N-Boc-glycine: 1H NMR (CD3-
OD) δ 8.19 (s, 1H), 7.62 (s, 2H), 7.23 (m, 6H), 5.35 (t, 1H),
4.47 (m, 1H), 2.76 (m, 2H), 2.50 (m, 2H), 1.27 (d, 3H); exact
mass (FAB, M + 1)+ calcd 436.1985, found 436.1987.
3-[[3-(5-Am id in o-2-in d oleca r b oxa m id o)-3-(t r iflu or o-
m eth yl)p r op ion yl]a m in o]-3-p h en ylp r op ion ic Acid (24).
Compound 24 was synthesized by the same method for 18
using N-Boc-R-(trifluoromethyl)-â-alanine in place of N-Boc-
glycine: 1H NMR (CD3OD) δ 8.20 (s, 1H), 7.64 (s, 2H), 7.30
(m, 6H), 5.27 (m, 2H), 2.80 (m, 4H); exact mass (FAB, M +
1)+ calcd 490.1702, found 490.1699.
6-Cya n o-1H-in d a zole-3-ca r boxylic Acid (15). To 6-cy-
anoindole (1.42 g, 10.0 mmol) suspended in a solution of
NaNO2 (6.9 g, 100 mmol) in H2O (200 mL) at room tempera-
ture was slowly added 6 N HCl (15 mL) until the pH was <2.
After the resulting suspension was stirred for 3 h, it was
extracted with EtOAc (5 × 150 mL). The EtOAc was dried
over MgSO4, filtered, and removed in vacuo to afford 3-formyl-
6-cyanoindazole (100%) which was subsequently oxidized
without further purification: 1H NMR (d6-DMSO) δ 10.2 (s,
1H), 8.35 (s, 1H), 8.25 (d, J ) 8.06 Hz, 1H), 7.65 (d, J ) 8.06
Hz, 1H); MS (EI) 171 (M+).
To a mixture of 3-formyl-6-cyanoindazole (10.0 mmol) and
2-methyl-2-butene (40 mL) in DMF (70 mL) at 0 °C was added
over 20 min a freshly prepared solution of NaClO2 (9 g, 0.10
mol) and NaH2PO4‚H2O (11 g, 80 mmol) in H2O (80 mL). This
reaction mixture was then stirred at room temperature until
complete by TLC and RP-HPLC. The reaction was acidified
by slow addition of 6 N HCl (40 mL) followed by stirring for 2
h. Water (250 mL) was added, and the solution was washed
with EtOAc (3 × 100 mL). The combined extracts were dried
(MgSO4) and solvent removed under reduced pressure to give
3 g of the crude acid. Trituration with 100 mL of DCM
followed by filtration and rinsing with an additional 50 mL of
DCM afforded 1.212 g (65% from 6-cyanoindole) of the title
compound 15 as an off-white solid: 1H NMR (d6-DMSO) δ 8.28
(s, 1H), 8.20 (d, J ) 6.0 Hz, 1H), 7.58 (d, J ) 6.1 Hz, 1H); MS
(EI) 187 (M+).

4316 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Su et al.
3-[[N-[(5-Am id in o-2-in d olyl)ca r b on yl]ison ip ecot yl]-
a m in o]-3-p h en ylp r op ion ic Acid (25). Compound 25 was
synthesized by the same method for 18 using N-Boc-isonipe-
cotic acid in place of N-Boc-glycine: 1H NMR (CD3OD) δ 8.18
(s, 1H), 7.61 (s, 2H), 7.30 (m, 6H), 5.33 (t, 1H), 4.50 (bs, 2H),
3.40 (m, 1H), 3.00 (m, 1H), 2.79 (m, 2H), 2.60 (m, 1H), 1.80
(m, 4H); exact mass (FAB, M + 1)+ calcd 462.2142, found
462.2144.
3-[[3-(5-Am idin o-2-in dolecar boxam ido)ben zoyl]am in o]-
3-p h en ylp r op ion ic Acid (26). Compound 26 was synthe-
sized by the same method for 18 using 3-Boc-aminobenzoic
acid in place of N-Boc-glycine: 1H NMR (CD3OD) δ 8.10-7.20
(m, 13H), 5.50 (m, 1H), 2.90 (m, 2H); exact mass (FAB, M +
1)+ calcd 470.1828, found 470.1829.
3-[[N-[(5-Am id in o-2-in d olyl)ca r bon yl]-L-p r olyl]a m in o]-
3-p h en ylp r op ion ic Acid (27). Compound 27 was synthe-
sized by the same method for 18 using N-Boc-L-proline in place
of N-Boc-glycine: 1H NMR (CD3OD) δ 8.10-7.20 (m, 9H), 5.35
(m, 1H), 4.23 (m, 1H), 3.29 (m, 2H), 2.80 (m, 2H), 1.93 (m,
4H); exact mass (FAB, M + 1)+ calcd 448.1985, found 448.1976.
3-[[2-(5-Am id in o-2-b en zofu r a n ca r b oxa m id o)a cet yl]-
a m in o]-3-p h en ylp r op ion ic Acid (28). Compound 28 was
synthesized by the same method for 18 using 5-(Cbz-amidino)-
benzofuran-2-carboxylic acid 7 in place of 5-(Cbz-amidino)-
indole-2-carboxylic acid 4: 1H NMR (CD3OD) δ 8.23 (s, 1H),
7.84 (m, 2H), 7.62 (s, 1H), 7.35 (m, 5H), 5.38 (t, 1H), 4.09 (s,
2H), 2.83 (m, 2H); exact mass (FAB, M + 1)+ calcd 409.1512,
found 409.1510.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-p h en ylp r op ion ic Acid (29). Compound 29 was
synthesized by the same method for 28 using N-Boc-â-alanine
in place of N-Boc-glycine: 1H NMR (CD3OD) δ 8.20 (s, 1H),
7.80 (dd, 2H), 7.59 (s, 1H), 7.30 (m, 2H), 7.18 (m, 3H), 5.39 (t,
1H), 3.62 (m, 2H), 2.80 (m, 2H), 2.59 (m, 2H); exact mass (FAB,
M + 1)+ calcd 423.1668, found 423.1673.
3-[[3-(N-Meth yl-5-a m id in o-2-ben zofu r a n ca r boxa m id o)-
p r op ion yl]a m in o]-3-p h en ylp r op ion ic Acid (30). Com-
pound 30 was synthesized by the same method for 28 using
N-Boc-N-methyl-â-alanine in place of N-Boc-glycine: 1H NMR
(CD3OD) δ 8.21 (m, 1H), 7.85 (m, 2H), 7.44 (s, 1H), 7.31 (m,
5H), 5.34 (m, 1H), 3.95 (m, 1H), 3.80 (m, 1H), 3.20 (s, 3H),
2.80 (m, 2H), 2.60 (m, 2H); exact mass (FAB, M + 1)+ calcd
437.1825, found 437.1822.
3-[[3-(5-Am id in o-2-ben zofu r a n ca r boxa m id o)-3-m eth yl-
p r op ion yl]a m in o]-3-p h en ylp r op ion ic Acid (31). Com-
pound 31 was synthesized by the same method for 28 using
N-Boc-R-methyl-â-alanine in place of N-Boc-glycine: 1H NMR
(CD3OD) δ 8.20 (s, 1H), 7.80 (m, 2H), 7.59 (d, 1H), 7.30 (m,
3H), 7.10 (m, 2H), 5.39 (t, 1H), 4.48 (t, 1H), 2.80 (m, 2H), 2.50
(m, 2H), 1.30 (d, 3H); exact mass (FAB, M + 1)+ calcd 437.1825,
found 437.1835.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]p r op ion ic Acid (36). Compound 36 was synthesized
by the same method for 29 using N-Boc-â-alanine hydroxym-
ethyl resin in place of D,L-3-(Boc-amino)-3-phenylpropionic acid
hydroxymethyl resin: 1H NMR (CD3OD) δ 8.23 (s, 1H), 7.82
(m, 2H), 7.60 (s, 1H), 3.65 (t, 2H), 3.42 (t, 2H), 2.50 (m, 4H);
exact mass (FAB, M + 1)+ calcd 347.1355, found 347.1362.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-(t r iflu or om et h yl)p r op ion ic Acid (37). Com-
pound 37 was synthesized by the same method for 29 using
D,L-N-Boc-amino-R-(trifluoromethyl)-â-alanine hydroxymethyl
resin in place of D,L-3-(Boc-amino)-3-phenylpropionic acid
hydroxymethyl resin: 1H NMR (CD3OD) δ 8.22 (s, 1H), 7.82
(m, 2H), 7.60 (s, 1H), 5.0 (t, 1H), 3.65 (t, 2H), 2.56 (m, 4H);
exact mass (FAB, M + 1)+ calcd 415.1229, found 415.1227.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-eth yn ylp r op ion ic Acid (38). Compound 38 was
synthesized by the same method for 29 using D,L-3-(Boc-
amino)-4-pentynoic acid 8f hydroxymethyl resin in place of D,L-
3-(Boc-amino)-3-phenylpropionic acid hydroxymethyl resin: 1H
NMR (CD3OD) δ 8.23 (s, 1H), 7.84 (t, 2H), 7.60 (s, 1H), 5.00
(m, 2H), 3.66 (m, 2H), 3.50 (m, 2H), 2.67 (s, 1H), 2.42 (t, 1H);
exact mass (FAB, M + 1)+ calcd 371.1355, found 371.1353.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-(3′-p yr id yl)p r op ion ic Acid (39). Compound 39
was synthesized by the same method for 29 using D,L-3-(Boc-
amino)-3-(3′-pyridyl)propionic acid 8e hydroxymethyl resin in
place of D,L-3-(Boc-amino)-3-phenylpropionic acid hydroxym-
ethyl resin: 1H NMR (CD3OD) δ 8.75 (s, 1H), 8.55 (d, 1H),
8.29 (m, 1H), 8.23 (s, 1H), 7.80 (m, 3H), 7.57 (s, 1H), 5.40 (t,
1H), 3.65 (t, 2H), 2.93 (m, 2H), 2.58 (m, 2H); exact mass (FAB,
M + 1)+ calcd 424.1621, found 424.1628.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
am in o]-3-(3′,4′-dim eth oxyph en yl)pr opion ic Acid (40). Com-
pound 40 was synthesized by the same method for 29 using
D,L-3-(Boc-amino)-3-(3′,4′-dimethoxyphenyl)propionic acid 8d
hydroxymethyl resin in place of D,L-3-(Boc-amino)-3-phenyl-
propionic acid hydroxymethyl resin: 1H NMR (CD3OD) δ 8.23
(s, 1H), 7.86 (dd, 2H), 7.55 (s, 1H), 6.90 (m, 2H), 6.76 (d, 1H),
5.32 (t, 1H), 3.67 (m, 2H), 2.78 (m, 2H), 2.58 (m, 2H); exact
mass (FAB, M + 1)+ calcd 483.1880, found 483.1882.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-(2′,5′-d iflu or op h en yl)p r op ion ic Acid (41). Com-
pound 41 was synthesized by the same method for 29 using
D,L-3-(Boc-amino)-3-(2′,5′-difluorophenyl)propionic acid 8a hy-
droxymethyl resin in place of D,L-3-(Boc-amino)-3-phenylpro-
pionic acid hydroxymethyl resin: 1H NMR (CD3OD) δ 8.22 (s,
1H), 7.84 (dd, 2H), 7.58 (s, 1H), 7.00 (m, 3H), 5.53 (t, 1H), 3.63
(t, 2H), 2.78 (m, 2H), 2.58 (m, 2H); exact mass (FAB, M + 1)+
calcd 459.1480, found 459.1486.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-(3′,4′-d iflu or op h en yl)p r op ion ic Acid (42). Com-
pound 42 was synthesized by the same method for 29 using
D,L-3-(Boc-amino)-3-(3′,4′-difluorophenyl)propionic acid 8b hy-
droxymethyl resin in place of D,L-3-(Boc-amino)-3-phenylpro-
pionic acid hydroxymethyl resin: 1H NMR (CD3OD) δ 8.22 (s,
1H), 7.82 (dd, 2H), 7.56 (s, 1H), 7.21 (m, 1H), 7.10 (m, 2H),
5.31 (t, 1H), 3.65 (m, 2H), 2.75 (m, 2H), 2.56 (m, 2H); exact
mass (FAB, M + 1)+ calcd 459.1480, found 459.1477.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-(3′,5′-d iflu or op h en yl)p r op ion ic Acid (43). Com-
pound 43 was synthesized by the same method for 29 using
D,L-3-(Boc-amino)-3-(3′,5′-difluorophenyl)propionic acid 8c hy-
droxymethyl resin in place of D,L-3-(Boc-amino)-3-phenylpro-
pionic acid hydroxymethyl resin: 1H NMR (CD3OD) δ 8.22 (s,
1H), 7.84 (dd, 2H), 7.58 (s, 1H), 6.92 (t, 2H), 6.71 (m, 1H), 5.32
(t, 1H), 3.65 (t, 2H), 2.77 (m, 2H), 2.58 (m, 2H); exact mass
(FAB, M + 1)+ calcd 459.1480, found 459.1483.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-3-(2-in d ol-3-yleth yl)p r op ion ic Acid (44). Com-
pound 44 was synthesized by the same method for 29 using
D,L-3-(N-Boc)-3-(2-(indol-3-yl)ethyl)-â-alanine 8g21 hydroxym-
ethyl resin in place of D,L-3-(Boc-amino)-3-phenylpropionic acid
hydroxymethyl resin: 1H NMR (CD3OD) δ 8.06 (d, 1H), 7.75
(t, 1H), 7.61 (t, 1H), 7.52 (s, 1H), 7.37 (t, 1H), 7.23 (t, 1H),
6.98 (t, 1H), 6.93 (s, 1H), 6.86 (t, 1H), 4.31 (m, 1H), 3.68 (m,
3-[[N-[(5-Am idin o-2-ben zofu r an yl)car bon yl]n ipecotyl]-
a m in o]-3-p h en ylp r op ion ic Acid (32). Compound 32 was
synthesized by the same method for 28 using N-Boc-nipecotic
acid in place of N-Boc-glycine: 1H NMR (CD3OD) δ 8.60 (s,
1H), 8.20 (s, 1H), 7.70 (m, 2H), 7.20 (m, 5H), 5.33 (t, 1H), 4.20
(m, 3H), 3.10 (m, 1H), 2.80 (m, 2H), 2.58 (m, 1H), 1.80 (m,
4H); exact mass (FAB, M + 1)+ calcd 463.1981, found 463.1977.
3-[[N-[(5-Am id in o-2-ben zofu r a n yl)ca r bon yl]-L-p r olyl]-
a m in o]-3-p h en ylp r op ion ic Acid (33). Compound 33 was
synthesized by the same method for 28 using N-Boc-L-proline
in place of N-Boc-glycine: 1H NMR (CD3OD) δ 8.22 (m, 1H),
7.83 (s, 1H), 7.00-7.60 (m, 7H), 5.34 (m, 1H), 5.00 (m, 1H),
4.11 (m, 1H), 3.75 (m, 1H), 2.80 (m, 2H), 2.20 (m, 4H); exact
mass (FAB, M + 1)+ calcd 449.1825, found 449.1820.
3-[[N-[(5-Am id in o-2-ben zofu r a n yl)ca r bon yl]-D-p r olyl]-
a m in o]-3-p h en ylp r op ion ic Acid (34). Compound 34 was
synthesized by the same method for 28 using N-Boc-D-proline
in place of N-Boc-glycine: 1H NMR (CD3OD) δ 8.20 (m, 1H),
7.80 (m, 1H), 7.00-7.60 (m, 7H), 5.34 (m, 1H), 5.00 (m, 1H),
4.11 (m, 1H), 3.75 (m, 1H), 2.80 (m, 2H), 2.20 (m, 4H); exact
mass (FAB, M + 1)+ calcd 449.1825, found 449.1825.
3-[[N-[(5-Am id in o-2-b en zofu r a n yl)ca r b on yl]t et r a h y-
dr oisoqu in olyl]am in o]-3-ph en ylpr opion ic Acid (35). Com-
pound 35 was synthesized by the same method for 28 using
N-Boc-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid in place
of N-Boc-glycine: MS (DCI) 511 (M + 1)+.

GPIIb-IIIa Antagonists Derived from 5,6-Bicyclic Templates
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4317
2H), 2.60 (m, 6H), 1.85 (m, 2H); exact mass (FAB, M + 1)+
calcd 490.2090, found 490.2080.
1.40 (q, 2H), 0.91 (t, 3H); exact mass (FAB, M + 1)+: calcd
481.1869, found 481.1873.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-2-a m in op r op ion ic Acid (45). Compound 45 was
synthesized by the same method for 29 using L-R-Z-â-Boc-
diaminopropionic acid hydroxymethyl resin in place of D,L-3-
(Boc-amino)-3-phenylpropionic acid hydroxymethyl resin: 1H
NMR (CD3OD) δ 8.23 (s, 1H), 7.85 (m, 2H), 7.80 (s, 1H), 3.70
(m, 5H), 2.51 (m, 2H); exact mass (FAB, M + 1)+ calcd
362.1464, found 362.1459.
3-[[3-(6-Am idin o-1H-3-in dazolecar boxam ido)pr opion yl]-
am in o]-2-[(bu tylsu lfon yl)am in o]pr opion ic Acid (55). Com-
pound 55 was synthesized by the same method for 53 using
compound 17 in place of 11: 1H NMR (CD3OD) δ 8.36 (d, 1H),
8.02 (s, 1H), 7.51 (d, 2H), 4.15 (dd, 1H), 3.65 (m, 2H), 3.27 (s,
2H), 2.95 (t, 2H), 2.51 (t, 2H), 1.67 (m, 2H), 1.35 (dd, 2H), 0.84
(t, 3H); exact mass (FAB, M + 1)+: calcd 482.1822, found
482.1817.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
am in o]-2-[(bu tylsu lfon yl)am in o]pr opion ic Acid (46). Com-
pound 46 was synthesized by the same method for 29 using
2(S)-[(n-butylsulfonyl)amino]-3-[N-(tert-butyloxycarbonyl)ami-
no]propionic acid22 hydroxymethyl resin in place of D,L-3-(Boc-
amino)-3-phenylpropionic acid hydroxymethyl resin: MS (ES)
482 (M + 1)+.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-2-[(p h en ylsu lfon yl)a m in o]p r op ion ic Acid (47).
Compound 47 was synthesized by the same method for 29
using 2(S)-[(phenylsulfonyl)amino]-3-[N-(tert-butyloxycarbo-
nyl)amino]propionic acid hydroxymethyl resin in place of D,L-
3-(Boc-amino)-3-phenylpropionic acid hydroxymethyl resin: 1H
NMR (CD3OD) δ 8.24 (s, 1H), 7.82 (m, 4H), 7.59 (m, 4H), 4.11
(t, 1H), 3.65 (m, 4H), 2.52 (m, 2H); exact mass (FAB, M + 1)+
calcd 502.1396, found 502.1383.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-2-[[(p-iod op h en yl)su lfon yl]a m in o]p r op ion ic Acid
(48). Compound 48 was synthesized by the same method for
29 using 2(S)-[[(p-iodophenyl)sulfonyl]amino]-3-[N-(tert-buty-
loxycarbonyl)amino]propionic acid hydroxymethyl resin in
place of D,L-3-(Boc-amino)-3-phenylpropionic acid hydroxym-
ethyl resin: 1H NMR (CD3OD) δ 8.23 (s, 1H), 7.85 (m, 4H),
7.64 (s, 1H), 7.55 (m, 2H), 3.92 (t, 1H), 3.65 (m, 4H), 2.53 (m,
2H); exact mass (FAB, M + 1)+ calcd 628.0363, found 628.0357.
3-[[3-(5-Am idin o-2-ben zofu r an car boxam ido)pr opion yl]-
a m in o]-2-[(d a n sylsu lfon yl)a m in o]p r op ion ic Acid (49).
Compound 49 was synthesized by the same method for 29
using 2(S)-[(dansylsulfonyl)amino]-3-[N-(tert-butyloxycarbo-
nyl)amino]propionic acid hydroxymethyl resin in place of D,L-
3-(Boc-amino)-3-phenylpropionic acid hydroxymethyl resin: 1H
NMR (CD3OD) δ 8.51 (d, 1H), 8.40 (d, 1H), 8.21 (m, 2H), 7.84
(m, 2H), 7.62 (m, 3H), 7.33 (d, 1H), 4.07 (t, 1H), 3.57 (m, 2H),
2.91 (s, 6H), 2.25 (m, 4H); exact mass (FAB, M + 1)+ calcd
595.1975, found 595.1988.
3-[[3-(6-Am id in o-2-in d oleca r boxa m id o)p r op ion yl]a m i-
n o]-3-p h en ylp r op ion ic Acid (50). Compound 50 was syn-
thesized by the same method for 18 using compound 11 in
place of 4, and manual solid-phase peptide synthesis (as
described in example 1) was utilized in place of the automated
system: MS (ES) 422 (M + 1)+.
3-[[3-(6-Am id in o-3-in d oleca r boxa m id o)p r op ion yl]a m i-
n o]-3-p h en ylp r op ion ic Acid (51). Compound 51 was syn-
thesized by the same method for 50 using compound 14 in
place of 11: 1H NMR(CD3OD) δ 8.30 (d, 1H), 8.03 (s, 1H), 7.95
(d, 1H), 7.54 (dd, 1H), 7.30 (dd, 2H), 7.19 (m, 3H), 5.36 (t, 1H),
3.64 (dq, 2H), 2.79 (dq, 2H), 2.56 (dd, 2H); exact mass (FAB,
M + 1)+ calcd 422.1828, found 422.1837.
3-[[3-(6-Am idin o-1H-3-in dazolecar boxam ido)pr opion yl]-
a m in o]-3-p h en ylp r op ion ic Acid (52). Compound 52 was
synthesized by the same method for 50 using compound 17 in
place of 11: 1H NMR(CD3OD) δ 8.45 (d, 1H), 8.10 (s, 1H), 7.58
(dd, 2H), 7.30 (dd, 2H), 7.26 (m, 3H), 5.35 (t, 1H), 3.69 (t, 2H),
2.77 (dq, 2H), 2.57 (t, 2H); exact mass (FAB, M + 1)+ calcd
422.1781, found 422.1779.
3-[[3-(6-Am id in o-2-in d oleca r boxa m id o)p r op ion yl]a m i-
n o]-2-[(bu tylsu lfon yl)a m in o]p r op ion ic Acid (53). Com-
pound 53 was synthesized by the same method for 46 using
compound 11 in place of 7, and manual solid-phase peptide
synthesis (as described in example 1) was utilized in place of
the automated system: MS (ES) 481 (M + H)+.
P la telet Aggr ega tion Assa ys. Platelet aggregation was
measured at 37 °C in a Chrono-log whole blood aggregometer
(Chrono-log Corp.; Havertown, PA) performed in human
platelet-rich plasma (PRP) prepared from blood of human
donors who had not taken aspirin within the previous 10 days.
Fifty-one milliliters of whole blood was drawn into 9 mL of
sodium citrate (3.8%) and centrifuged at 160g for 20 min and
allowed to stand for 5 min, and PRP was decanted into a clean
tube. Platelet poor plasma (PPP) was prepared from the PRP
by further centrifugation at 2000g for 10 min, removed with
a pipet, and used in the reference cell of the aggregometer.
Test substances dissolved in water or 5% aqueous DMSO were
added to PRP to a final volume of 0.5 mL and allowed to
incubate for 1 min followed by the addition of ADP (20 µM
final) to initiate aggregation. Platelet aggregation was quan-
titated by measuring the total amplitude on a chart recorder.
IC50 values were determined from dose-response curves
generated from various concentrations of the purified com-
pounds added to PRP.
Solid -P h a se Liga n d Bin d in g Assa ys. The effect of
compounds on the binding of adhesive proteins to GPIIb-IIIa
and Rvâ3 were determined using the solid-phase microtiter
assays as described.31,32 Purified integrins were added to
microtiter wells of enzyme-linked immunosorbant assay plates
(Immunlon II, Dynatech, Inc.) at 1 µg/well in 100 µL of buffer
A (20 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1 mM CaCl2, 0.02%
azide) and incubated overnight at 4 °C. At the time of the
experiment, the wells were washed with buffer B (50 mM Tris-
HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl2, 0.02% azide) and
100 µL/well of buffer B plus 35 mg/mL BSA added for 2-3 h
at room temperature to block nonspecific binding. After this
incubation, the plate was washed with buffer B plus 1 mg/mL
BSA. Biotinylated adhesive proteins were added to wells at
a final concentration of 20 nM along with various concentra-
tions of test compounds and the plate incubated at room
temperature for 3 h. The plate was again washed in buffer B
plus 1 mg/mL BSA and bound biotinylated protein quantified
by the addition of Sigma mouse anti-biotin antibody (100 µL/
well of 1:2500 dilution) conjugated to alkaline phosphatase.
Following a 1 h room temperature incubation, the wells were
washed with buffer B plus 1 mg/mL BSA, and 100 µL of the
substrate p-nitrophenyl phosphate was added (Bio-Rad kit).
The color development was read after 10 min on a Molecular
Devices plate reader at 405 nm.
Or a l Dosin g of P r od r u gs to Ra ts. Sprague-Dawley rats
were fasted overnight and dosed by oral gavage. The com-
pounds (56-58) were formulated in 50% poly(ethylene glycol)
300 at 3 mg/mL and administered at 10 mg/kg. Blood was
collected under Isoflurane anesthesia into 3.8% trisodium
citrate (9:1) and plasma was prepared for subsequent analysis
by HPLC.
P la sm a An a lysis P r oced u r e. Plasma (0.2 mL) was mixed
with 0.8 mL of pH 2 phosphate buffer containing internal
standard and then extracted using IST Isolute C2 (EC)
extraction cartridges. The extracts were analyzed by HPLC
using an acetonitrile/pH 3 sodium dodecyl sulfate mobile phase
and an Inertsil 150 × 3.2 mm column maintained at 40 °C
with UV detection at 235 nm. The standard curves for
analogues 30 and 46 were linear from 10 to 5120 ng/mL.
3-[[3-(6-Am id in o-3-in d oleca r boxa m id o)p r op ion yl]a m i-
n o]-2-[(bu tylsu lfon yl)a m in o]p r op ion ic Acid (54). Com-
pound 54 was synthesized by the same method for 53 using
compound 14 in place of 11: 1H NMR (CD3OD) δ 8.32 (d, 1H),
8.15 (s, 1H), 7.94 (dd, 1H), 7.55 (dd, 1H), 4.21 (dd, 1H), 3.68
(m, 2H), 3.32 (t, 2H), 3.02 (t, 2H), 2.54 (t, 2H), 1.74 (m, 2H),
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