Fused bicyclic Gly-Asp β-turn mimics with specific affinity for GPIIb- IIIa

Article abstract of DOI:10.1021/jm990365y

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure activity studies centered on the bicyclic β-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6,5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.

Full text of DOI:10.1021/jm990365y

J . Med. Chem. 1999, 42, 4875-4889
4875
F u sed Bicyclic Gly-Asp â-Tu r n Mim ics w ith Sp ecific Affin ity for GP IIb-IIIa
†
‡
Matthew J . Fisher,* Ann E. Arfstan, Ulrich Giese, Bruce P. Gunn, Cathy S. Harms, Vien Khau,
‡
‡
Michael D. Kinnick, Terry D. Lindstrom, Michael J . Martinelli, Hans-J u¨ rgen Mest, Michael Mohr,
J ohn M. Morin, J r., J effrey T. Mullaney, Anne Nunes, Michael Paal, Achim Rapp, Gerd R u¨ hter,
Ken J . Ruterbories, Daniel J . Sall, Robert M. Scarborough, Theo Schotten, Birgit Sommer, Wolfgang Stenzel,
Richard D. Towner, Suzane L. Um, Barbara G. Utterback, Robert T. Vasileff, Silke V o¨ elkers,
‡
‡
‡
†
‡
‡
‡
‡
Virginia L. Wyss, and J oseph A. J akubowski
Eli Lilly and Company, Indianapolis, Indiana 46028, Lilly Research Laboratories, Hamburg, Germany, and COR
Therapeutics, Inc., South San Francisco, California 94080
Received J uly 15, 1999
Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further
structural evaluation. Structure-activity studies centered on the bicyclic â-turn mimic contained
in these molecules indicated that this moiety could accommodate a variety of modifications.
Specifically, monocyclic, 6,5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity
for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei
yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere
(
benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage,
although the latter enhances activity. Several compounds in this series provided measurable
blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester
generally provided compounds which gave greater systemic exposure after oral administration.
Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin,
tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.
In tr od u ction
design of non-peptide GPIIb-IIIa antagonists. Initial
compounds employed an isoquinolone moiety as a â-turn
mimic with the aspartate and arginine side chains
attached at the 2- and 6-positions, respectively. Struc-
ture-activity studies (SAR) in this series demonstrated
that potent GPIIb-IIIa receptor antagonism could be
obtained with compounds that contained an acetic acid
residue at C2 and a benzamidine tethered from C6 of
the isoquinolone nucleus. Data from this investigation
suggested that 2,6-disubstituted isoquinolones 2 and 3
were leads suitable for further investigation (Figure 1).40
The design and development of agents which control
thrombosis by modulating platelet aggregation has
received significant attention over the past decade. The
primary physiological role of the platelet is to copoly-
merize with fibrinogen and thus aggregate at sites of
injury forming a hemostatic plug that seals off leaks in
the vasculature. It has been shown that the membrane-
associated glycoprotein (GP) IIb-IIIa is primarily re-
sponsible for this aggregation phenomenon.
1
2
3
-5
This
receptor, which is a member of a family of adhesive
proteins collectively known as integrins, binds to Arg-
Gly-Asp (RGD) sequences contained in the soluble
Originally, our choice of an isoquinolone nucleus was
based on the fact that its overall shape closely resembled
the Gly-Asp â-turn determined for peptide 1 and that
the resident functionality of this ring system allowed
ready attachment of the arginine and aspartate side
chains. As our initial investigations focused solely on
side chain optimization, we remained interested in the
SARs afforded by the supporting nucleus. We were
particularly interested to see if a monocyclic analogue
of our lead isoquinolone would have activity, and within
the constraints of a bicyclic â-turn mimic, we were
interested in what effect would result from changing the
size of the ring to which the aspartate isostere was
appended. Finally, the functionality within the B-ring
(see Figure 1) of our isoquinolone leads also offered
several readily accessible areas for modification. We
sought to understand the role of the cyclic amide and
probe ring conformation by evaluating compounds with
differing hybridization at C2 and C3 of the bicyclic
nucleus. Key goals for this investigation were to gain
insight into the relationship between the â-turn mimic
and in vitro activity and to determine if active com-
pounds from this series would afford measurable plasma
plasma protein fibrinogen.6
-9
This critical interaction
between GPIIb-IIIa and fibrinogen can be inhibited by
either acyclic or cyclic RGD-containing peptides.
These observations have formed the basis for the use
of the RGD motif as a lead structure in the design of
novel inhibitors of platelet aggregation.20-36
1
0-19
We have recently described our initial studies toward
the design and refinement of non-peptide antagonists
of GPIIb-IIIa.37,38 Our approach was initiated with the
preparation of small cyclic peptides which incorporated
an RGD sequence, yielding a family of compounds with
high affinity for GPIIb-IIIa.39 We subsequently evalu-
1
ated one of the most potent peptides (1) by H NMR and
determined that in aqueous solution, the critical RGD
sequence in this molecule primarily exists in a well-
defined type II′ Gly-Asp â-turn.38 This conformation,
which defined the relationship of the critical arginine
and aspartate side chains, formed the foundation for our
‡
Lilly Research Laboratories.
COR Therapeutics, Inc.
†
1
0.1021/jm990365y CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/23/1999

4
876 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Fisher et al.
F igu r e 1. Lead peptide 1 and derived non-peptide â-turn mimics 2 and 3. Activity data for compounds 2 and 3 are located in
Tables 2 and 3, respectively.
Sch em e 1a
a
(a) EEDQ, tert-butylglycine; (b) Triton B, R-bromo-p-tolunitrile; (c) H2S, MeI, NH4OAc, Boc2O; (d) TFA.
levels in animals following oral administration. For this
study, we chose to initially examine relevant structural
modifications in the oxo-linked series since the required
synthetic intermediates for the desired target molecules
were readily accessible. Structural motifs that provided
greater intrinsic activity than the lead oxo-linked iso-
quinolone 2 were then synthesized and evaluated in the
more active amide-linked series. In this report, we
disclose our observations regarding the in vitro SARs
that we have defined for the â-turn mimic contained in
our lead isoquinolones 2 and 3 and report on the oral
activity of the most potent compounds prepared in this
series.
of these compounds selectively on oxygen was ac-
complished with R-bromo-p-tolunitrile using Triton B
which provided the monosubstituted intermediates 13
and 14. Alkylation of the lactam nitrogen contained in
these molecules was effected by first deprotonating with
NaH and then quenching the resultant anion with tert-
butyl bromoacetate which yielded disubstituted com-
pounds 15 and 16. These materials were then trans-
formed into the desired amidino acids 19 and 20 using
protocols similar to that outlined for the preparation of
8.
One example of an unsaturated isoquinolone was
prepared as outlined in Scheme 3. Treatment of 5-meth-
oxyindanone with sodium methoxide and butyl nitrite
afforded a mixture of the desired isoquinolone 23 and
Ch em istr y
4
3
The synthesis of the monocyclic derivative of isoqui-
nolone 2 is illustrated in Scheme 1. 4-Hydroxybenzoic
acid (4) and tert-butylglycine were coupled using EEDQ,
producing amide 5. The phenol moiety in this molecule
was then alkylated with R-bromo-p-tolunitrile which
provided adduct 6. The nitrile moiety was subsequently
converted into a Boc-protected amidine (7) using a
oxime 22. Treatment of 23 with aqueous HI at reflux
effected reduction of the hydroxamic acid and demethy-
lation of the C6-methoxy group providing intermediate
24 in good yield. This material was transformed into
the desired 2,6-difunctionalized compound 28 by utiliz-
ing a sequence similar to that described for the prepara-
tion of 8.
3
8
modified thio-Pinner sequence previously described.
Compound 37, which contains an isomeric 3-oxoiso-
quinolone nucleus, was synthesized as shown in Scheme
Simultaneous deprotection of the tert-butyl ester and
the Boc-amidine moieties with neat TFA provided the
desired amidino acid 8 as the TFA salt.
4
4
4. Treatment of lactone 29 with saturated methanolic
HBr provided bromo ester 30. This material was reacted
directly with lithium azide to afford intermediate 31.
The crude product from this reaction was immediately
treated with triphenylphosphine which formed lactam
32 as a crystalline solid. This intermediate was trans-
formed into the desired target compound 37 by func-
tionalization at the 2- and 6-positions in a manner
Compounds in which the B-ring of isoquinolone 2 (see
Figure 1) was expanded or contracted by one carbon
were prepared as described in Scheme 2. Demethylation
4
1
of methoxyisoindol-1-one 9 and methoxybenzazepin-
-one 1042 was accomplished with BBr3 at room tem-
perature which provided phenols 11 and 12. Alkylation
1

Fused Bicyclic Gly-Asp â-Turn Mimics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4877
Sch em e 2a
a
(a) BBr3; (b) Triton B, R-bromo-p-tolunitrile; (c) NaH, tert-butyl bromoacetate; (d) H2S, MeI, NH4OAc, Boc2O; (e) TFA.
Sch em e 3a
a
(
a) NaOMe, butyl nitrite; (b) HI reflux; (c) R-bromo-p-tolunitrile, K2CO3; (d) NaH, tert-butyl bromoacetate; (e) H2S, MeI, NH4OAc,
Boc2O; (f) TFA.
analogous to that previously described for the prepara-
tion of compound 8.
Compounds that contain either a 6-oxo- or 6-ami-
noisoquinoline were prepared from the known isoqui-
nolone intermediates 38 and 39 as outlined in Scheme
TFA salt prior to alkylation of the intermediate thio-
amide with excess methyl iodide. This modification of
our standard sequence allowed for the preparation of
the desired Boc-protected amidines 46 and 49 in rea-
sonable yield. Deprotection of these compounds was
accomplished with neat TFA, which provided the target
molecules 47 and 50 as the corresponding salts.
5
. Reduction of these compounds with LAH yielded the
requisite isoquinoline derivatives 40 and 41. Function-
alization of the secondary nitrogen in these molecules
was accomplished by alkylation with tert-butyl bro-
moacetate in the presence of K2CO3 affording 42 and
The methods used for the construction of compounds
containing tetralone nuclei are outlined in Schemes 6
and 7. Preparation of compound 56, which contains a
6-oxotetralone nucleus begins with the condensation of
6-hydroxytetralone (51) and glyoxylic acid in the pres-
4
6
3. The p-cyanophenyl moiety was appended to the
-position of 43 and 44 via alkylation or acylation to
4
5
afford 45 and 48, respectively. Amidine formation in this
series was complicated by the fact that the tertiary
amine present in these molecules was susceptible to
quaternization during the course of our standard thio-
Pinner sequence. Thus, we protected the amine as its
ence of NaOH which afforded adduct 52. The R,â-
unsaturated ester was reduced with zinc and acetic acid,
and the formed saturated carboxylic acid was subse-
quently converted to ester 53 by treatment with diphe-
nyl diazomethane. Phenol 53 was then alkylated with

4
878 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Fisher et al.
Sch em e 4a
a
(
a) HBr/MeOH; (b) lithium azide; (c) Ph3P; (d) NaH, tert-butyl bromoacetate; (e) Pd/C; (f) R-bromo-p-tolunitrile, K2CO3; (g) H2S, MeI,
NH4OAc, Boc2O; (h) TFA.
Sch em e 5a
a
(
a) LAH; (b) tert-butyl bromoacetate, K2CO3; (c) H2, Pd/C; (d) R-bromo-p-tolunitrile; (e) p-cyanobenzoic acid, EDCI; (f) H2S, TFA-MeI,
NH4OAc, Boc2O, (g) TFA.
R-bromo-p-tolunitrile which provided the 2,6-disubsti-
tuted compound 54. Conversion of the nitrile moiety in
this molecule to a Boc-protected amidine (55) was
accomplished using protocols similar to that described
for the preparation of 8. Simultaneous deprotection of
the ester and amidine functional groups was accom-
plished with neat TFA to afford the desired amidino acid
using the same conditions outlined for the preparation
of 8. Treatment of this material with aqueous LiOH in
THF afforded the protected amidino acid 62 after careful
neutralization. This material was not characterized;
rather it was subjected to deprotection with neat TFA
yielding amidino acid 63 as a white solid.
The construction of compounds that contain tetralin
nuclei is outlined in Schemes 8 and 9. Synthesis of a
2-substituted-6-oxotetralin began with the reaction of
commercially available 6-methoxytetralone (64) with the
sodium salt of triethyl phosphonoacetate which provided
ester 65 as a mixture of olefin isomers. Saturation of
the double bond was accomplished with hydrogen in the
presence of palladium on carbon, and the 6-methoxy
5
6 as the TFA salt.
Synthesis of the 6-amino-1-tetralone (Scheme 7)
began with acidic hydrolysis of the acetamide contained
4
5
in the tetralone 57. This material was then esterified
with ethanolic HCl which provided aniline 58. Acylation
of aniline 58 with 4-cyanobenzoic acid yielded 59, which
was then converted to the Boc-protected amidine 60

Fused Bicyclic Gly-Asp â-Turn Mimics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4879
Sch em e 6a
a
(a) NaOH, glyoxylic acid; (b) Zn, HOAc; (c) diphenyl diazomethane; (d) R-bromo-p-tolunitrile; (e) H2S, MeI, NH4OAc, Boc2O; (f) TFA.
Sch em e 7a
a
(a) Aqueous HCl; (b) HCl/EtOH; (c) p-cyanobenzoic acid/EDCI; (d) H2S, MeI, NH4OAc, Boc2O; (e) LiOH, (f) TFA.
Sch em e 8a
Synthesis of the 6-aminotetralin 79 began by reduc-
tion of 72 with NaBH4 forming the corresponding
benzylic alcohol, which was subsequently dehydrated
with TsOH in refluxing toluene to yield olefin 73. This
material was then allowed to react with OsO4 to produce
vicinal diol 74. Treatment of a toluene solution of 74
with TsOH at reflux produced an intermediate 2-tetra-
lone which was not purified; rather it was reacted crude
with the sodium salt of tert-butyl diethyl phosphonoac-
etate which provided a mixture of olefin isomers 75.
Catalytic hydrogenation of this material afforded the
desired 6-aminotetralin 76 in good yield. Conversion of
this intermediate into the desired product 79 was
accomplished in a manner similar to that outlined for
the preparation of 63.
a
(a) Methyl diethyl phosphonoacetate; (b) H2, Pd/C; (c) BBr3;
(
d) R-bromo-p-tolunitrile; (e) H2S, MeI, NH4OAc, Boc2O; (f) NaOH;
(g) TFA.
Compounds that contain a benzopyran nucleus were
prepared as outlined in Schemes 10 and 11. Preparation
of ether-linked derivative 84 began with alkylation of
group was demethylated with BBr3. Phenol 67 was
alkylated with R-bromo-p-tolunitrile which provided the
4
6
2
,6-disubstituted tetralin 68. Conversion of the nitrile
the known 6-hydroxybenzopyran 80 with R-bromo-p-
tolunitrile which afforded intermediate 81. This com-
pound was converted first to the Boc-protected amidine
82 and then to the fully deprotected compound 84 using
the protocol described for the preparation of 63. Syn-
thesis of the amide-linked congener of 84 began with
moiety of 68 to a Boc-protected benzamidine was ac-
complished with standard thio-Pinner conditions. Con-
version of intermediate 69 into the desired amidino acid
7
1 was accomplished using procedures similar to that
employed for the preparation of compound 63.

4
880 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Fisher et al.
Sch em e 9a
a
(a) NaBH4; (b) TsOH; (c) OsO4; (d) TsOH; (e) tert-butyl diethyl phosphonoacetate; (f) Pd/C, H2; (g) p-cyanobenzoic acid, EDCI; (h) H2S,
MeI, NH4OAc, Boc2O; (i) TFA.
Sch em e 10a
be achieved after oral dosing. Selected compounds were
also evaluated for cross-reactivity with RVâ3 in an
ELISA type assay that measured the inhibition of
vitronectin binding to purified immobilized human
vitronectin receptor (RVâ3).
Evaluation of the â-turn mimic contained in our initial
lead compounds began with an effort to define the
relationship between the size of the aliphatic ring (B-
ring) and activity (Table 1). Monocyclic compound 8 was
found to be 8-fold less potent in the ELISA assay (IC50
)
5.0 µM) than the biclycic congener 2 from which it
was modeled. Compound 19, which contains a 6,5-ring
system, provided 4-fold greater activity than monocyclic
compound 8 but 2-fold less activity than its one-carbon
homologue 2. Disubstituted benzazepine 20 was 8-fold
more potent than either the monocyclic compound 8 or
the compound containing a 6,5-nucleus (19).
We next investigated the contributions of the func-
tionality contained in the lactam ring of 2 (Table 2).
Introduction of unsaturation at positions 3 and 4 yielded
derivative 28 which was found to be 7-fold less potent
in the ELISA (IC50 ) 4.2 µM) than its saturated
congener. Shifting the amide carbonyl of isoquinolone
a
(
a) K2CO3, R-bromo-p-tolunitrile; (b) H2S, MeI, NH4OAc,
Boc2O; (c) NaOH; (d) TFA.
the palladium-catalyzed hydrogenation of commercially
available 6-nitrocoumarin (85) in the presence of di-tert-
butyl dicarbonate which provided compound 86. Partial
reduction of the lactone 86 with DIBAH gave rise to an
intermediate lactol that was immediately reacted with
(
ethoxycarbonyl)triphenylphosphorane which yielded
benzopyran 87. The Boc group was then removed with
TFA giving rise to aniline 88. Acylation of this material
with 4-cyanobenzoic acid provided the 2,6-disubstituted
benzopyran 89. Benzamidine formation in this series
was accomplished using the same protocol described for
the tetralone 63. Formation of the parent compound 93
was accomplished by first hydrolyzing the ester with
aqueous NaOH and then removing the amidine protect-
ing group with TFA.
2
from the 1-position to the 3-position provided isomeric
isoquinolone 37, which was determined to be 10-fold less
active in the ELISA (IC50 ) 5.8 µM) than the 1-oxo
derivative 2. Reduction of the lactam of 2 provided
isoquinoline 47 which is 20-fold more potent in the
ELISA (IC50 ) 0.033 µM) than the corresponding 1-oxo
compound 2. Replacement of the isoquinolone nitrogen
of 2 by carbon affords tetralone 56 which was roughly
equipotent with 47 in the ELISA assay and has similar
activity in PRP. Removal of all functionality in the
B-ring of 2 provides tetralin derivative 71 which was
2-fold more potent in the ELISA (IC50 ) 0.26 µM) than
2 but 10-fold less active than either 47 or 56. Benzopy-
ran 84 provided potency similar to isoquinoline 47 and
tetralone 56 and greater activity than either 2 or the
tetralin derivative 71.
These data demonstrate that the oxo-linked tetralin
(71), tetralone (56), isoquinoline (47), and benzopyran
(84) nuclei afford compounds with greater affinity for
GPIIb-IIIa than the lead isoquinolone 2. We therefore
chose to evaluate these nuclei in the amide-linked series
(Table 3). As expected from previous studies, amide-
linked isoquinoline 50 afforded a 6-fold increase in
Resu lts
Compounds were evaluated for receptor affinity in an
ELISA type assay that measured the inhibition of
biotinylated fibrinogen binding to immobilized human
GPIIb-IIIa. Compounds with sufficient activity in this
assay (IC50 < 0.5 µM) were then examined in a func-
tional assay that measured the agents’ ability to inhibit
aggregation of human platelets activated by ADP (5 µM)
in human platelet-rich plasma (PRP). Compounds 2 and
, which were developed during our previous investiga-
tions, served as activity references for this study.
Compounds with IC50 values less than 0.2 µM in PRP
were further evaluated in vivo in rats and/or guinea pigs
in an effort to determine if measurable blood levels could
3
3
8

Fused Bicyclic Gly-Asp â-Turn Mimics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4881
Sch em e 11a
a
(a) Pd/C, Boc2O; (b) DIBAH; (c) (ethoxycarbonyl)triphenylphosphorane; (d) TFA; (e) 4-cyanobenzoic acid, EDCI; (f) H2S, MeI, NH4OAc,
Boc2O; (g) NaOH.
Ta ble 1. Activity Data for Compounds with Varying Ring Size
Ta ble 2. Activity Data for 6-Oxo-Linked Compounds with
Varying Nuclei
a
Concentration required to reduce binding of fibrinogen to
purified human GPIIb-IIIa by 50%. The IC50 values are expressed
as the average of at least two determinations. The average error
for the IC50 determinations was (15%.
GPIIb-IIIa binding affinity (ELISA IC50 ) 0.005 µM)
and a 2-fold activity increase in PRP (IC50 ) 0.17 µM)
relative to 47. Activity gains were also observed for the
amide-linked tetralin derivative 79 which was roughly
5
1
0-fold more active in the ELISA (IC50 ) 0.005 µM) and
70-fold more potent in PRP (IC50 ) 0.19 µM) than its
oxo-linked counterpart 71. Replacement of the ether
linkage with an amide linkage was also beneficial for
the tetralone derivative 63 as well. Activity increased
in the ELISA by 16-fold (IC50 ) 0.002 µM) and by 7.5-
fold in PRP (IC50 ) 0.06 µM) relative to 56. Intrinsic
activity for benzopyran 93 was found to be similar to
that for other amide-linked compounds (ELISA IC50 )
a
As in Table 1. b Concentration required to reduce ADP-induced
human platelet aggregation response by 50%. The IC50 values are
expressed as the average of at least two determinations. The
average error for the IC50 determinations was (16%. nd, not
determined.
0
.002 µM) with functional activity comparable to that
interest by determining the plasma concentrations and
degree of exposure (as defined by the area under the
curve (AUC) for the time course studied) which resulted
from a single oral dose. We were unable to use phar-
macodynamic (platelet aggregation) measurements for
these studies since pilot experiments with rodent plate-
lets indicate that several of the more potent compounds
showed poor inhibition of ADP-induced platelet ag-
gregation in rodent PRP (data not shown). This is
of analogues 50 and 79 but slightly less than that of
isoquinolone 3 or tetralone 63.
The compounds described in Table 3 all afforded in
vitro activity in human PRP sufficient for further
evaluation in vivo. Since one of our goals was the
development of agents that would provide pharmaco-
logical concentrations of antagonist in plasma after oral
administration, we further evaluated compounds of

4
882 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Fisher et al.
Ta ble 5. Conversion of Parent Free Acids to Ester Prodrugs
Ta ble 3. Activity Data for 6-Amide-Linked Compounds with
Varying Nuclei
a
Concentration required to reduce binding of fibrinogen to
purified human GPIIb-IIIa by 50%. b Concentration required to
reduce ADP-induced human platelet aggregation response by 50%.
Ta ble 4. Blood Level Data Obtained After a Single 10 mg/kg
Oral Dose in the Guinea Pig
compd
nucleus
ester AUC (ng‚h/mL) Cmax (ng/mL)
3
isoquinolone
tetralin
none
none
ethyl
ethyl
ethyl
ethyl
400
903
543
3697
1583
3988
126
252
177
1167
469
1147
F igu r e 2. Plasma concentration of tetralin 79 in guinea pig
following a single oral dose (10 mg/kg) of various ester
prodrugs.
7
9
9
9
6
9
4
6
9
1
a
isoquinolone
a
tetralin
a
isoquinoline
tetralone
a
pounds as the hydrochloride salt. Oral administration
of the ethyl ester analogue of 3 (94) provided a 1.4-fold
improvement of the Cmax (177 ng/mL) of the parent
isoquinolone 3 and a 1.3-fold increase in the AUC for
the 0-5-h time course studied. Conversion of tetralin
derivative 79 to the ethyl ester prodrug 96 provided
more substantial gains in that the Cmax increased by
4.6-fold (3697 ng/mL) and the AUC increased by 4-fold.48
Encouraged by these results, we then evaluated the
impact that the alkyl portion of the ester had on
exposure in the tetralin series. Simple alkyl ester
homologues of 96 were evaluated orally at 10 mg/kg in
the guinea pig, and the results are shown in Figure 2.
These data indicate that the alkyl portion of the ester
moiety can affect exposure. Each ester derivative pro-
vided an increase in AUC relative to the parent acid
with the ethyl analogue proving to be optimum of those
tested. As a result, we continued our oral testing efforts
with compounds in which the carboxylate was esterified.
We focused our efforts on ethyl ester analogues as this
modification provided the greatest increase in AUC
relative to the parent acid for the tetralin and because
the alcohol product of ester hydrolysis is presumably
less toxic.
a
Tabulated values derived from detection and analysis of parent
free acid in plasma.
consistent with previous reports of species specificity
with GPIIb-IIIa antagonists.47 Accordingly, we devised
a pharmacokinetic approach in which compound blood
levels were determined by HPLC analysis at 1-, 2-, and
-h time points. We chose to test compounds of interest
in the guinea pig and/or rat after a single oral dose of
5
1
0 mg/kg.
Analysis of isoquinolone 3 in the guinea pig according
to the above protocol indicated that measurable blood
levels (Table 4) were achieved after oral administration
of 10 mg/kg. The observed Cmax was 126 ng/mL, and
AUC for the 5-h time period was 400 ng‚h/mL. Results
for the tetralin 79 were approximately 2-fold greater
with a Cmax of 252 ng/mL and an AUC for the 5 h of
9
03 ng‚h/mL. While these results were encouraging, the
moderate plasma levels obtained with amidino acids 3
and 79 suggested that the extent of oral absorption was
poor. We hypothesized that the zwitterionic character
of these molecules might be in part responsible for the
limited exposure obtained after oral dosing. We there-
fore elected to test this possibility by masking the
carboxylate moiety found in 3 and 79 as an ester
prodrug.
The ethyl ester of isoquinoline 50 (99) afforded a 2.9-
fold increase in AUC relative to the related isoquinolone
ester 94 but provided roughly one-half the exposure of
the tetralin ester 96. Tetralone ester 61 provided an
exposure profile that was equivalent to that of tetralin
96 and better than that of either isoquinolone 94 or
isoquinoline 99. The tetralin ester 96 and tetralone ester
61 were further studied orally at 10 mg/kg in the rat
Esterification was readily accomplished by dissolving
the parent amidino acid in the desired alcohol and then
treating the resulting solution with excess anhydrous
HCl (see Table 5). Isolation was accomplished by
concentration which provided the desired prodrug com-

Fused Bicyclic Gly-Asp â-Turn Mimics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4883
Ta ble 6. Blood Levels Obtained After a Single 10 mg/kg Oral
Dose of Compounds 96, 61, and 91 in the Rat
is also seen for compound 19 which contains a 6,5-ring
system. The role of the amide functionality in the B-ring
of 2 was probed by moving the amide carbonyl from
position 1 to position 3. Examination of models indicates
that this transposition of the amide carbonyl changes
the conformation of the B-ring from essentially flat to
that of a boat, thus imparting a cup shape to the
molecule. The lower activity afforded by 37 suggests
that the conformation provided by this lactam isomer
is less desirable than that of the related isoquinolone
2.
compd
nucleus
tetralin
tetralone
ester
AUC (ng‚h/mL) Cmax (ng/mL)
a
9
6
9
6
1
1
ethyl
ethyl
15910
11243
14835
5055
3630
4850
a
a
benzopyran ethyl
a
See note on Table 4.
(Table 6). Comparison of the data in Tables 4 and 6
demonstrates that the tetralone 61 and tetralin 96
behaved similarly in both species. However, the data
shows that the rat provides somewhat higher levels of
exposure after oral administration of these compounds.
The ethyl ester of benzopyran 93 (91) produced an AUC
of 14835 ng‚h/mL and a Cmax of 4850 ng/mL in the rat
which was comparable to that achieved with 61 and 96.
Encouraged by these results, we chose to determine
the absolute bioavailability of the tetralin 96, tetralone
The SARs afforded by the B-ring were further exam-
ined in the oxo-linked series with the incorporation of
3
sp hybridization at C1 and C2. These modifications
afforded an increase in ELISA activity relative to
2
isoquinolone 2. Removal of the sp character provided
by the amide moiety allows the B-ring in these 6,6-
systems to adopt a twist-chair conformation. Compari-
son of models of compounds 47, 56, and 71 (assuming
that the aspartate isostere will occupy the pseudoequa-
torial position) reveals that the aspartate isostere adopts
an overall topography similar to that of isoquinolone 2.
In contrast to the lactam leads, the B-ring of these latter
compounds provides additional conformational flex-
ibility, which may be in part responsible for the increase
in potency observed for these molecules.
6
1, and benzopyran 91 in the rat. This was accom-
plished by determining a companion pharmacokinnetic
profile which resulted from an intravenous administra-
tion of the parent free acid of each ester analogue.
Comparison of the oral and intravenous exposure pro-
files for these compounds affords an absolute bioavail-
ability in the rat of 28%, 23%, and 24% for the tetralin
9
6, tetralone 61, and benzopyran 91, respectively. The
bioavailability afforded by these compounds makes them
attractive candidates for further investigations. As a
prelude to these studies, the parent acids of the tetralin
In the oxo-linked series, the functionality contained
in the B-ring had some influence on activity. Isoquino-
line 47 demonstrates that an additional basic residue
proximal to the aspartate isostere is well-tolerated.
Comparison of the activity data derived from the iso-
quinoline 47 and tetralone 56 with the tetralin deriva-
tive 71 indicates that the polar functionality at C1 or
C2 in the former compounds improved activity. This
observation is consistent with the fact that benzopyran
9
6 (79), tetralone 61 (63), and benzopyran 91 (93) were
evaluated for cross-reactivity with the related integrin
RVâ3. No appreciable binding was observed at micro-
molar concentrations indicating that these compounds
have high selectivity for human GPIIb-IIIa.
Discu ssion
8
4 affords greater activity than tetralin 71.
Replacement of the bicyclic â-turn mimic found in lead
isoquinolone 2 with a monocyclic derivative affords
compound 8, which has measurable affinity for GPIIb-
IIIa (IC50 ) 6 µM) but is approximately 10-fold less
active than its bicyclic congener. Comparison of com-
pounds 2 and 8 reveals that the overall distance
between the acidic and basic moieties, and their spatial
relationship, is approximately the same for these two
compounds, thus accounting for the activity observed
for monocyclic compound 8. The data does however
suggest that the conformational restriction afforded by
the bicyclic motif contained in 2 is advantageous for
activity in this family of molecules. Within the bicyclic
series, the size of the B-ring (see Figure 1) also appears
to be a factor that influences activity. The data dem-
onstrates that a ring size of five (19) provides lower
affinity for GPIIb-IIIa than ring sizes of six (2) or seven
In accord with our earlier findings, linkage of the
benzamidine to the supporting nucleus through an
amide bond provides an increase in activity over an
ether linkage. It is however interesting to note that in
the amide-linked series, all nuclei provided similar
intrinsic activity. This is in contrast to what was
observed in the oxo-linked series where lack of polar
functionality in the B-ring (compare 71 with 56 and 84)
2
3
and sp rather than sp hybridization at C2 (compare 2
with 47 and 56) negatively impact activity. The amide
linkage, in effect, provides the opportunity to incorpo-
rate a wider variety of functional groups into the â-turn
mimic without sacrificing activity.
The data presented in this report are consistent with
the literature in that they demonstrate a variety of
central constraints can be employed in the design and
preparation of compounds with affinity for GPIIb-IIIa.1
Recently, a number of similarly substituted bicyclic
(20).
2
9,33,40
Incorporation of unsaturation into the lactam ring
inhibitors have been described.
The design of these
provides compound 28 which was 7-fold less potent than
the lead isoquinolone 2. While the structural difference
between these two compounds initially appears mini-
mal, comparison of models of isoquinolone 2 with the
unsaturated compound 28 demonstrates that the lactam
ring of this latter compound is less flexible, effectively
forcing the aspartate isostere to reside coplanar with
the aromatic A-ring. A similar coplanar relationship
between the aromatic ring and the aspartate isostere
compounds generally follows from structural informa-
tion obtained during the spectroscopic analysis of potent
RGD-containing cyclic peptides. These reports have
suggested that a turn-extended-turn conformation of the
RGD sequence predominates in solution for the peptides
2
9,33
examined.
Several studies have demonstrated that
mimicking this conformation with a bicyclic nucleus that
is angularly substituted (see Figure 3) with an arginine
and aspartate isostere affords compounds with exquisite

4
884 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Fisher et al.
F igu r e 3. Comparison of turn-extended-turn and Gly-Asp conformational models.
potency and selectivity.29,33 As we have discussed, our
design strategy utilized a Gly-Asp conformation, which
requires a linear substitution of the bicyclic â-turn
mimic. The activity data for the linearly substituted
compounds contained in this report demonstrate that
a Gly-Asp conformation can also be utilized as a tool in
the design of potent inhibitors of GPIIb-IIIa.
had been masked by esterification.48 Examination of the
data contained in Figure 2 suggests that the nature of
the ester prodrug can have an effect on oral availability.
The observed trend for the tetralin series indicates that
oral exposure decreased as the size of the alkyl portion
of the ester increased. While we were able to obtain µg/
mL blood levels with several molecules in this series,
we were unable to look for efficacy surrogates in either
the rat or guinea pig as these compounds have greatly
diminished activity toward platelets from these species
relative to that from humans. However, the fact that
the human PRP IC50 values for the compounds listed
in Table 3 range from 20 to 70 ng/mL indicates that if
exposure in humans was similar, a single oral dose of
10 mg/kg would provide supra pharmacological plasma
concentrations of active agent.
Okumura et al. have demonstrated that 2,7-substi-
tuted 6,6-bicyclic nuclei also can be effectively utilized
4
0
in the design of potent antagonists of GPIIb-IIIa. We
have previously shown that the combination of an ether-
linked benzamidine and an isoquinolone nucleus was
sensitive to substitution patterns, with 2,6-substitution
(linear) providing higher affinity for GPIIb-IIIa than 2,7-
substitution (angular). Comparison of the data in this
report with that disclosed40 suggests that this observa-
tion may not be generalized to include all 6,6-nuclei. The
fact that both 2,6- and 2,7-substituted nuclei can be
optimized to yield potent inhibitors of GPIIb-IIIa pro-
vides additional evidence to support the notion that
Con clu sion
We have demonstrated that a variety of potent
inhibitors of GPIIb-IIIa can be obtained through sys-
tematic modification of the lactam ring contained in lead
isoquinolones 2 and 3. We have demonstrated that this
series of compounds benefits from a bicyclic central
nucleus and that isoquinoline, tetralin, tetralone, and
benzopyran ring systems provide active molecules. SARs
suggest that completely planar ring systems in this
series are less effective. Greater activity is observed with
a variety of bicyclic ring systems that provide a B-ring
which affords some conformational flexibility. Activity
also appears to benefit from the incorporation of a polar
group at positions C1 or C2 of the bicyclic core. Linkage
of the benzamidine moiety to the supporting nucleus
with an amide provides greater potency than the cor-
responding ether linkage, and activity for the amide-
linked series is less sensitive to structural manipulation
of the â-turn mimic.
Measurable blood levels were obtained after oral
dosing of two of the most potent amidino acids. Exposure
levels were however modest, and in an effort to improve
this, the compounds were given as the corresponding
ester prodrugs. These compounds, which lack the zwit-
terionic character possessed by the parent amidino acid,
provided increased exposure. Evaluation of a series of
amide-linked ester prodrugs in both the rat and guinea
pig identified several compounds that provided sub-
stantial blood levels after oral administration of 10 mg/
4
9
GPIIb-IIIa contains an extended cation binding site.
While potency has been an important end point for
all of these studies, selectivity for GPIIb-IIIa has also
been a consideration. It is known that the RGD motif
is recognized by other integrins, such as the closely
related integrin RVâ3, and it has been suggested that
ligand specificity among these receptors may be a
function of the conformation afforded by the RGD
sequence (or RGD mimic) in question.5
0,51
It has been
proposed that a Gly-Asp motif is an important design
element to consider for the preparation of compounds
5
2
with selectivity for RVâ3 relative to GPIIb-IIIa. In
contrast to this proposal, we have determined that
several of our Gly-Asp mimics provide potent affinity
for GPIIb-IIIa with little or no cross-reactivity for RVâ3.
These data suggest that the presence of a Gly-Asp
conformation in an RGD mimic is insufficient to confer
selectivity for RVâ3 relative to GPIIb-IIIa.
Examination of the data presented in Tables 4 and 6
indicates that all of the compounds evaluated in this
study provided measurable plasma levels after oral
administration of 10 mg/kg. Isoquinolone 3 and tetralin
7
9 provided maximum blood levels of 126 and 252 ng/
mL, respectively. Consistent with other observations in
the literature, our results indicate that greater exposure
was obtained with compounds in which the acid moiety

Fused Bicyclic Gly-Asp â-Turn Mimics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4885
kg. Efforts are underway to evaluate selected com-
pounds for efficacy in a relevant animal model, and
these studies will be reported shortly.
4-[[4-(Am in oim in om et h yl)p h en yl]m et h oxy]b en zoyl-
glycin e Tr iflu or oa ceta te (8). A solution of 7 (0.20 g, 0.42
mmol) in 4 mL of TFA was stirred at room temperature for 3
h. The solvent was removed in vacuo and the residue triturated
with Et
white powder: H NMR (300 MHz, DMSO-d
H), 9.3 (s, 2H), 9.0 (s, 2H), 8.7 (t, 1H, J ) 6 Hz), 7.85 (t, 4H,
2
O and dried in vacuo to afford 0.16 g (90%) of 8 as a
Exp er im en ta l Section
1
6
) δ 12.55 (br s,
1
All starting materials were commercially available or previ-
ously reported in the literature unless noted. All reactions were
run in an atmosphere of dry nitrogen, and solvents and
reagents were used without purification with the exception of
THF which was distilled from sodium/benzophenone. Nuclear
magnetic resonance spectra for characterization of synthesis
products were recorded at 300 MHz on GE QE-300 and Bruker
AC-300 spectrometers or at 400 MHz on a Varian Mercury
spectrometer. Chemical shifts are reported in parts per million
relative to tetramethylsilane. High-resolution mass spectra
were recorded on a VG Analytical ZAB2-SE instrument, and
FD mass spectra were recorded on a MAT-731 instrument.
Infrared spectra were recorded on a Nicolet DX10 FT-IR
spectrometer with the medium noted in the individual experi-
ment. Melting points were recorded on a Thomas-Hoover
melting point apparatus and are uncorrected. Elemental
analyses were performed at Lilly Research Laboratories by the
Physical Chemistry Department and are within (0.4% of
theory unless otherwise noted.
J ) 8 Hz), 7.7 (d, 2H, J ) 8 Hz), 7.1 (d, 2H, J ) 8 Hz), 5.35 (s,
2
1
1
H), 3.9 (d, 2H, J ) 6 Hz); IR (KBr) 3332, 3106, 1737, 1670,
637, 1607, 1575, 1548, 1505, 1450, 1420, 1390, 1305, 1262,
191, 1133, 1044, 844; MS (FAB) m/e 328. Anal. (C19
18 3 6 3
H N O F )
C,H,N.
6
-Am in o-1,2,3,4-tetr a h yd r oisoqu in olin ea cetic Acid 1,1-
5
2
Dim eth yl Ester (44). A mixture of 6-aminoisoquinolone (40)
(
1.0 g, 6.17 mmol) and lithium aluminum hydride (0.18 g, 18.5
mmol) in THF (50 mL) was maintained at reflux for 72 h. The
mixture was then treated sequentially with H O (0.185 mL),
5% NaOH (0.185 mL), and H
O (0.55 mL).52 The resulting
2
1
2
mixture was filtered and the filtrate concentrated to dryness.
The residue was chromatographed on silica gel (25% MeOH/
CHCl to 25% MeOH/10% Et N/CHCl ) which afforded 0.6 g
3 3 3
of the desired amine 41 as a yellow semisolid. This material
darkened appreciably upon standing and, as a result, was used
immediately in the next step.
A portion of the material obtained in the previous step (0.20
4
-Hyd r oxyben zoylglycin e 1,1-Dim eth yleth yl Ester (5).
-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (19.7
g, 79.6 mmol) was added to a solution of 4-hydroxybenzoic acid
4) (10.0 g, 72.4 mmol) in 400 mL of CH CN and 100 mL of
g, 1.35 mmol) was treated with a mixture of tert-butyl
2
bromoacetate (0.2 mL, 1.35 mmol), K
and CH CN (3 mL). After stirring for 24 h at room tempera-
ture, the above mixture was diluted with EtOAc (50 mL) and
washed with H
O (3 × 10 mL). The organic material was dried
(K CO ) and concentrated. Chromatography on silica gel
(EtOAc:TEA:MeOH, 90/5/5) provided 0.24 g (70%) of 44 as a
white powder: 1H NMR (400 MHz, CDCl
) δ 1.45 (s, 9H), 2.79
2 3
CO (0.19 g, 1.35 mmol),
3
(
3
THF at room temperature. The mixture was stirred at room
temperature for 0.25 h; then glycine tert-butyl ester (9.5 g, 72.4
mmol) was added, and the mixture stirred at room tempera-
ture for 72 h. The solvent was removed in vacuo. The residue
was diluted with EtOAc, washed with 1 N HCl, H
saturated aqueous NaHCO , and then extracted five times
with 1 N NaOH. The combined aqueous extracts were washed
with EtOAc, acidified to pH 2 with concentrated HCl, and
extracted five times with methylene chloride. The combined
organic extracts were washed with saturated brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated to
2
2
3
3
O, and
(s, 4H), 3.25 (s, 2H), 3.64 (s, 2H), 6.38 (d, J ) 2.4 Hz, 1H),
6.43 (dd, J ) 2.4, 8.3 Hz, 1H), 6.76 (d, J ) 8.2 Hz, 1H); IR
2
3
-
1
3
(CHCl ) 3007, 1736, 1624, 1369, 1150 cm ; MS (ES) m/e 263
+
(MH ). Anal. (C15
22 2 2
H N O ) C,H,N.
6-[(4-Cya n oben zoyl)a m in o]-1,2,3,4-tetr a h yd r oisoqu in -
olin ea cetic Acid 1,1-Dim eth yleth yl Ester (48). A solution
of 44 (0.038 g, 0.144 mmol), 4-cyanobenzoic acid (0.021 g, 0.144
mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hy-
drochloride (0.041 g, 0.217 mmol), DMAP (cat.), and CH Cl
1
afford 4.5 g (25%) of 5 as a white solid: H NMR (300 MHz,
DMSO-d ) δ 10.0 (s, 1H), 8.55 (br t, 1H, J ) 6 Hz), 7.75 (d,
6
2
2
2
1
1
7
H, J ) 8 Hz), 6.82 (d, 2H, J ) 8 Hz), 3.85 (d, 2H, J ) 6 Hz),
(2 mL) was maintained at room temperature for 12 h. The
.4 (s, 9H); IR (KBr) 3396, 3123, 2982, 1725, 1636, 1602, 1581,
544, 1508, 1435, 1382, 1367, 1290, 1232, 1182, 11698, 855,
solution was diluted with EtOAc (50 mL), washed with H O,
2
and then concentrated. Chromatography (silica gel, EtOAc)
provided 0.034 g (60%) of 48 as a white solid: 1H NMR (CDCl3,
300 MHz) δ 1.49 (s, 9H), 2.95 (m, 4H), 3.33 (s, 2H), 3.79 (s,
2H), 7.03 (d, J ) 8.2 Hz, 1H), 7.30 (d, J ) 8.1 Hz, 1H), 7.45 (s,
1H), 7.75 (d, J ) 8.1 Hz, 2H), 7.95 (d, J ) 8.1 Hz, 2H); IR
-
1
75 cm ; MS (FD) m/e 251. Anal. (C13
-[(4-Cya n op h en yl)m et h oxy]b en zoylglycin e 1,1-Di-
m eth yleth yl Ester (6). Triton B (40% in methanol) (1.88 mL,
.18 mmol) was slowly added to a solution of 5 (1.00 g, 3.98
mmol) in 50 mL of DMF at -5 °C. The mixture was stirred at
4
H17NO ) C,H,N.
4
4
-
1
(KBr) 3300, 2233, 1730, 1647, 1153 cm ; MD (FD) m/e 391.
Anal. (C23 ) C,H,N.
-
5 °C for 0.5 h; then R-bromo-p-tolunitrile (0.82 g, 4.18 mmol)
25 3 3
H N O
was added, and the resultant mixture was stirred at -5 °C
6-[[4-[[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]im in o-
m eth yl]ben zoyl]a m in o]-1,2,3,4-tetr a h yd r oisoqu in olin e-
a cetic Acid 1,1-Dim eth yleth yl Ester (49). A solution of 48
(0.10 g, 0.265 mmol) in triethylamine (1 mL) and pyridine (10
for an additional 4 h. The reaction mixture was diluted with
EtOAc, washed three times each with 1 N HCl, H
NaOH, H O, and saturated brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The oily white
residue was recrystallized twice from EtOAc/Et O to afford
.83 g (57%) of 6 as a white solid: H NMR (300 MHz, DMSO-
2
O, 1 N
2
mL) was saturated with H S(g) and allowed to stand at room
2
2
temperature overnight. The solution was then diluted with
1
0
H O and the resulting mixture was extracted with EtOAc (3
2
d
6
) δ 8.66 (br t, 1H, J ) 6 Hz), 7.8 (m, 4H), 7.62 (d, 2H, J ) 8
× 25 mL). The extracts were combined and concentrated. The
crude residue was taken up in acetone and treated with
trifluoroacetic acid (0.05 mL, 0.53 mmol) and methyl iodide
(0.08 mL, 1.33 mmol). The resulting solution was maintained
at 60 °C for 2 h and then concentrated to dryness. The
resulting solid was taken up in MeOH (1 mL) and treated with
Hz), 7.05 (d, 2H, J ) 8 Hz), 5.25 (s, 2H), 3.82 (d, 2H, J ) 6
Hz), 1.36 (s, 9H); IR (KBr) 3388, 2229, 1735, 1643, 1607, 1533,
1
5
504, 1369, 1252, 1232, 1178, 1153, 1019, 880, 837, 827, 765,
58 cm ; MS (FD) m/e 366. Anal. (C21
4
-
1
22 2 4
H N O ) C,H,N.
-[[4-[[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]im in o-
m eth yl]p h en yl]m eth oxy]ben zolyglycin e 1,1-Dim eth yl-
eth yl Ester (7). This compound was prepared starting from
nitrile 6 by employing the thio-Pinner sequence previously
anhydrous NH
maintained at 60 °C for 2 h and then concentrated. This
material was dissolved in THF/H O (1:1 10 mL) and treated
with K CO (0.22 g, 1.59 mmol) and di-tert-butyl dicarbonate
(0.29 g, 1.32 mmol). After 1 h at room temperature, this
mixture was diluted with EtOAc (50 mL), washed with H O,
4
OAc (0.051 g, 0.66 mmol). This solution was
2
3
8 1
described: H NMR (300 MHz, CDCl
Hz), 7.66 (d, 2H, J ) 8 Hz), 7.3 (d, 2H, J ) 8 Hz), 7.2(m, 2H),
3
) δ 7.8 (d, 2H, J ) 8
2
3
6
4
3
1
4
.85 (br t, 1H, J ) 6 Hz), 6.82 (d, 2H, J ) 8 Hz), 5.0 (s, 2H),
.02 (d, 2H, J ) 6 Hz), 1.44 (s, 9H), 1.43 (s, 9H); IR (KBr)
374, 2979, 1745, 1617, 1576, 1532, 1503, 1456, 1392, 1367,
280, 1252, 1226, 1164, 1017, 999, 843, 768 cm-1; MS (EI) m/e
2
and then concentrated. Chromatography (silica gel, hexanes-
1
EtOAc, 1:4) provided 0.34 g of 49 as a white foam: H NMR
(400 MHz, CDCl
3.29 (s, 2H), 3.74 (s, 2H), 6.96 (d, J ) 8.2 Hz, 1H), 7.39 (br d,
3
) δ 1.47 (s, 9H), 1.52 (s, 9H), 2.87 (m, 4H),
84. Anal. (C26
33 3 6
H N O ) C,H,N.

4
886 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Fisher et al.
J ) 8.2 Hz, 1H), 7.43 (s, 1H), 7.82 (s, 4H), 8.18 (br s, 1H); IR
precipitate was collected by filtration and dried under vacuum.
This material was then dissolved in TFA (10 mL) and allowed
to stand for 1 h at room temperature. The material was then
-
1
+
(
KBr) 1730, 1550, 1421, 1153 cm ; MS (FAB) m/e 509 (MH ).
Anal. (C23 ) C,H,N.
-[[[4-(Am in oim in om et h yl)p h en yl]ca r b on yl]a m in o]-
,2,3,4-tetr a h yd r oisoqu in olin ea cetic Acid Tr iflu or oa c-
36 4 5
H N O
6
concentrated and the residue was triturated with Et
a solid which was collected by filtration: 1H NMR (300 MHz,
CD
2
O forming
1
eta te (50). This compound was prepared from 49 using the
3
OD) δ 2.0 (m, 1H), 2.25 (m, 1H), 2.50 (dd, J ) 6.4,16.5 Hz,
same procedure employed for the preparation of 8: 1H NMR
1H), 2.86 (dd, J ) 5.8, 16.5 Hz, 1H), 2.90-3.20 (m, 3H), 7.62
(dd, J ) 1.9, 8.6 Hz, 1H), 7.78 (s, 1H), 7.94 (m, 3H), 8.14 (d, J
(
4
1
300 MHz, CD
3
OD) δ 3.26 (m, 2H), 3.65 (m, 2H), 4.11 (s, 2H),
.50 (s, 2H), 7.20 (d, J ) 8.47 Hz, 1H), 7.61 (m, 2H), 7.72 (s,
H), 7.92 (d, J ) 8.3 Hz, 2H), 8.12 (d, J ) 8.2 Hz, 2H); IR
-
1
) 8.3 Hz, 2H); IR (KBr) 3330, 3108, 1669, 1538 cm ; MS
(FAB) m/e 366. Anal. (C22
20 3 6 3
H N O F ) C,H,N.
-
1
(
(
KBr) 3301, 1672, 1202, 1135 cm ; MS (FAB) m/e 353. Anal.
) C,H,N.
-Am in o-1,2,3,4-t et r a h yd r o-1-oxon a p h t h a len e-2-a ce-
7-[[(P h en ylm eth oxy)car bon yl]am in o]-1,2-dih ydr on aph -
th ylen e (73). A solution of 7245 (5.0 g, 16.9 mmol) and EtOH
23 22 4 7 6
C H N O F
6
(30 mL) was treated with NaBH
temperature. After 5 h, the solution was diluted with H
4
(0.64 g, 16.9 mmol) at room
O (100
4
5
tic Acid Eth yl Ester (58). A mixture of 57 (20 g, 77.2 mmol)
2
and concentrated HCl (100 mL) was maintained at reflux for
mL) and extracted with EtOAc (3 × 50 mL). The extracts were
combined and concentrated. The crude residue was taken up
in benzene (50 mL) and treated with TsOH (0.1 g). The
resulting mixture was maintained at reflux for 1 h with
0
.5 h and then allowed to cool to room temperature. This
mixture was diluted with H O (300 mL) and cooled to 0 °C.
The mixture was neutralized to pH 4 by the careful addition
of solid Na CO . The formed precipitate was collected by
2
removal of H
The mixture was diluted with EtOAc (300 mL) and washed
with saturated aqueous NaHCO . The organic material was
dried (MgSO ), filtered, and concentrated. Chromatography
(silica gel, hexanes-EtOAc, 3:1) provided 3.9 g of 73 as a white
solid: 1H NMR (300 MHz, CDCl
) δ 2.27 (m, 2H), 2.78 (t, J )
2
O and then allowed to cool to room temperature.
2
3
filtration and dried in vacuo. This material was dissolved in
EtOH (250 mL) and the formed solution was saturated with
HCl (g). After 2 h, the solution was concentrated to dryness
3
4
in vacuo. The formed solid was dissolved in H
2
O and the
mixture saturated with NaHCO . This mixture was then
3
3
extracted with EtOAc and the extracts were combined and
concentrated. The crude solid was recrystallized from EtOAc/
8.13 Hz, 2H), 5.21 (s, 2H), 5.97 (m, 1H), 6.42 (d, J ) 9.6 Hz,
1H), 6.65 (br s, 1H), 6.96 (d, J ) 8.1 Hz, 1H), 7.12 (d, J ) 8.1
hexanes giving 10.0 g of 58 as a tan solid (mp 122-124 °C):
Hz, 1H), 7.21 (s, 1H), 7.38 (m, 5H); IR (KBr) 3307, 1718, 1694,
1
-1
H NMR (400 MHz, CDCl
H), 2.14 (m, 1H), 2.34 (m, 2H), 2.80 (m, 1H), 2.95 (m, 3H),
.13 (q, J ) 7.1 Hz, 2H), 6.38 (s, 1H), 6.52 (dd, J ) 1.8, 8.3
3
) δ 1.14 (t, J ) 7.1 Hz, 3H), 1.92 m,
2
1535, 1228 cm ; MS (FD) m/e 279. Anal. (C18H17NO ) C,H,N.
1
4
1,2-Dih yd r oxy-6-[[(p h en ylm eth oxy)ca r bon yl]a m in o]-
1,2,3,4-tetr a h yd r on a p h th ylen e (74). A mixture of 73 (3.9
g, 13.97 mmol) N-methylmorpholine N-oxide (2.07 g, 15.37
Hz, 1H), 7.85 (d, J ) 8.3 Hz, 1H); IR (KBr) 1743, 1654, 1579,
1
-1
357 cm ; MS (FAB) m/e 248.1293 (248.1286 calcd for C14
H
18
-
mmol), tert-butyl alcohol (7.5 mL), acetone (7.5 mL), H O (10
2
NO
3
).
mL), and OsO (cat.) was stirred at room temperature for 6 h.
4
6
-[[(4-Cyan oph en yl)car bon yl]am in o]-1,2,3,4-tetr ah ydr o-
The mixture was then diluted with EtOAc (100 mL) and
washed sequentially with 1 N aqueous sodium bisulfite and
1
-oxon a p h th ylen e-2-a cetic Acid Eth yl Ester (59). This
compound was prepared using the protocol outlined for the
H
2
O. The organic material was dried (MgSO
4
), filtered, and
concentrated affording 74 as a white solid: H NMR (300 MHz,
CDCl ) δ 1.87 (m, 1H), 1.95 (m, 1H), 2.74 (m, 1H), 2.90 (m,
1
1
preparation of compound 48: H NMR (300 MHz, CDCl
1
1
3
) δ
.27 (t, J ) 7.1 Hz, 3H), 2.0 (m, 1H), 2.25 (m, 1H), 2.45 (m,
H), 3.15 (m, 4H), 4.20 (q, J ) 7.1 Hz, 2H), 7.25 (s, 1H), 7.34
3
1H), 3.97 (m, 1H), 4.62 (d, J ) 3.9 Hz, 1H), 5.16 (s, 2H), 6.69
(br s, 1H), 7.12 (d, J ) 8.3 Hz, 1H), 7.21 (s, 1H), 7.35 (m, 6H);
IR (KBr) 3419, 33.21, 1741, 1713, 1545, 1224 cm ; MS (FD)
(
d, J ) 8.5 Hz, 1H), 7.81 (d, J ) 8.1 Hz, 2H), 8.01 (d, J ) 8.1
-
1
Hz, 2H), 8.05 (d, J ) 8.6 Hz, 1H); IR (KBr) 3309, 2233, 1716,
-1
1
685, 1584, 1540 cm ; MS (FAB) m/e 377. Anal. (C22
C,H,N.
-[[[4-[[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]im in o
H
20
N
2
O
4
)
4
m/e 313. Anal. (C18H19N0 ) C,H,N.
P r od u ct Mixtu r e 75. A mixture of diol 74 (1.33 g, 4.24
6
mmol), TsOH (cat.), and toluene (20 mL) was heated at reflux
m et h yl]p h en yl]ca r b on yl]a m in o]-1,2,3,4-t et r a h yd r o-1-
oxon a p h th ylen e-2-a cetic Acid Eth yl Ester (60). This
compound was prepared from 59 using the thio-Pinner se-
with removal of H O for 1 h and then allowed to cool to room
2
temperature. The solution was then washed with 0.1 N NaOH,
dried (K CO ), and concentrated. In a separate reaction vessel,
2
3
3
8 1
quence previously reported: H NMR (300 MHz, CDCl
1
1
3
) δ
.29 (t, J ) 7.1 Hz, 3H), 1.59 (s, 9H), 2.0 (m, 1H), 2.22 (m,
H), 2.45 (m, 1H), 3.0 (m, 4H), 4.20 (q, J ) 7.1 Hz, 2H), 7.40
a mixture of diethyl tert-butyl phosphonoacetate (1.6 g, 6.37
mmol), NaH (0.25 g of a 60% dispersion in oil, 6.37 mmol),
and THF (10 mL) was allowed to react and then cooled to -78
°C. A THF (10 mL) solution of the crude dehydration product
was then added and the resulting mixture was allowed to
warm to room temperature. The reaction mixture was diluted
(
dd, J ) 2.1, 8.6 Hz, 1H), 7.80-7.95 (m, 5H), 8.05 (d, J ) 8.6
-1
Hz, 1H), 8.32 (br s, 1H); IR (KBr) 3434, 1736, 1669, 1147 cm
;
MS (FAB) m/e 522. Anal. (C27
-[[[4-(Am in oim in om et h yl)p h en yl]ca r b on yl]a m in o]-
,2,3,4-tetr a h yd r o-1-oxon a p h th ylen e-2-a cetic Acid Eth yl
31 3 6
H N O ) C,H,N.
6
with EtOAc (50 mL) and washed with H
2
O (2 × 20 mL). The
1
organic material was dried (MgSO ), filtered, and concentrated.
4
Ester Hyd r och lor id e (61). This compound was prepared
from 60 by treatment with neat TFA at room temperature for
Chromatography (silica gel, hexanes-EtOAc, 5:1) provided 0.7
g of 75 as a clear oil. Characteristic data for the product
mixture: 1H NMR (400 MHz, CDCl
) δ 1.43 (s, 9H), 2.29 (br t,
1
h followed by concentration. The crude material was then
3
dissolved in 1 N aqueous HCl and lyophilized giving the
desired ester 61 as the hydrochloride salt: H NMR (300 MHz,
J ) 8.3 Hz, 2H), 2.79 (br t, J ) 8.3 Hz, 2H), 3.07 (s, 2H), 5.17
(s, 2H), 6.25 (s, 1H), 6.61 (br s, 1H), 6.89 (d, J ) 7.8 Hz, 1H),
7.05 (d, J ) 8.3 Hz, 1H), 7.24 (br s, 1H), 7.35 (m, 5H); IR
1
CD OD) δ 1.24 (t, J ) 7.3 Hz, 3H), 1.97 (m, 1 h), 2.20 (m, 1H),
3
-
1
2
1
8
.24 (dd, J ) 6.2, 16.4 Hz, 1H), 2.79 (dd, J ) 6.3 Hz, 16.4 Hz,
H), 3.0 (m, 3H), 4.12 (q, J ) 7.3 Hz, 2H), 7.63 (dd, J ) 1.8,
.5 Hz, 1H), 7.77 (s, 1H), 7.89 (d, J ) 8.2 Hz, 1H), 7.94 (d, J
(CHCl
3
) 1725, 1521, 1369, 1145, 1055 cm ; MS (ES) m/e 394
) C,H,N.
(MH+). Anal. (C24
H
27NO
4
6-Am in o-2-tetr a lin a cetic Acid 1,1-Dim eth yleth yl Ester
(76). A mixture of 75 (1.5 g, 3.81 mmol), Pd/C (10%, 1.0 g),
and EtOH (30 mL) was stirred under an atmosphere of H2
(balloon) for 2 h, then filtered, and concentrated. The crude
residue was purified by chromatography (silica gel, hexanes-
)
8.2 Hz, 2H), 8.15 (d, J ) 8.2 Hz, 2H); IR (KBr) 3094, 1730,
-1
1
697, 1536, 1277 cm ; MS (FAB) m/e 394. Anal. (C22
Cl) C,H,N.
-[[[4-(Am in oim in om et h yl)p h en yl]ca r b on yl]a m in o]-
,2,3,4-tetr a h yd r o-1-oxon a p h th ylen e-2-a cetic Acid Tr i-
24 3 4
H N O -
6
1
1
EtOAc, 2:1) giving 0.77 g (77%) of 76 as a clear oil: H NMR
flu or oa ceta te (63). A mixture of 60 (0.10 g, 0.19 mmol),
NaOH (0.015 g, 0.383 mmol), and EtOH (5 mL) was main-
tained at room temperature for 4 h and then concentrated.
(300 MHz, CDCl
3
) δ 1.4 (m, 1H), 1.47 (s, 9H), 1.95 (m, 1H),
2.1-2.3 (m, 3H), 2.40 (m, 1H), 2.75 (m, 3H), 6.45 (s, 1H), 6.49
(d, J ) 8.1 Hz, 1H), 6.86 (d, J ) 8.0 Hz, 1H); IR (CHCl
3
) 1719,
-
1
The residue was taken up in H
2
O (10 mL) and carefully
. The formed
1624, 1506, 1149 cm ; MS (FAB) m/e 262. Anal. (C16
0.15H O) C,H,N.
H
2
23NO ‚
neutralized (pH 5) with 10% aqueous KHSO
4
2

Fused Bicyclic Gly-Asp â-Turn Mimics
-[(4-Cya n oben zoyl)a m in o]-2-tetr a lin a cetic Acid 1,1-
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4887
to 80:20, v/v) to yield 51 g of 87 (76%): 1H NMR (400 MHz,
6
Dim eth yleth yl Ester (77). A mixture of 76 (1.18 g, 4.52
mmol), 4-cyanobenzoic acid (0.73 g, 4.97 mmol), EDCI (1.29
3
CDCl ) δ 6.99 (br s, 1H), 6.70 (dd, J ) 8.9 Hz, 2.5 Hz, 1H),
6.48 (d, J ) 8.9 Hz, 1H), 6.16 (s, 1H), 4.21 (m, 1H), 3.98 (q, J
) 7.2 Hz, 2H), 2.64 (ddd, J ) 16.5 Hz, 10.4 Hz, 5.2 Hz, 1H),
2.55 (dd, J ) 15.4 Hz, 7.4 Hz, 1H), 2.52 (ddd, J ) 16.5 Hz, 5.2
Hz, 4.1 Hz, 1H), 2.36 (dd, J ) 15.4 Hz, 6.1 Hz, 1H), 1.84 (dm,
J ) 13.5 Hz, 1H), 1.54 (m, 1H), 1.29 (s, 9H), 1.07 (t, J ) 7.2
g, 6.78 mmol), and CH
temperature for 2 h. The mixture was then diluted with EtOAc
150 mL), washed with H
O (2 × 25 mL), and concentrated.
Chromatography (silica gel, 3:1 hexanes/EtOAc) provided 1.38
2 2
Cl (5 mL) was stirred at room
(
2
1
-1
g (78%) of 77 as a white solid: H NMR (300 MHz, CDCl
1
1
3
) δ
.48 (s, 9H), 1.46 (m, 1H), 1.95 (m, 1H), 2.25 (m, 3H), 2.45 (m,
H), 2.95 (m, 3H), 7.05 (d, J ) 8.2 Hz, 1H), 7.28 (d, J ) 8.2
Hz, 3H); IR (KBr) 3358, 1736, 1698, 1526, 1238 cm ; MS (ES)
5
m/e 335. Anal. (C18H25NO ) C,H,N.
6-Am in o-2[2H]-ch r om a n ea cetic Acid Eth yl Ester (88).
A mixture of 87 (1.0 g, 2.98 mmol) was dissolved in anhydrous
TFA (10 mL) and allowed to stand at room temperature for 1
h. This solution was then concentrated to dryness and the
Hz, 1H), 7.41 (s, 1H), 7.76 (d, J ) 8.2 Hz, 2H), 7.88 (br s, 1H),
7
1
.98 (d, J ) 8.2 Hz, 1H); IR (KBr) 2980, 2234, 1719, 1647,
-
1
149 cm ; MS (FD) m/e 390. Anal. (C24
26 2 3
H N O ) C,H,N.
6
-[[[4-[[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]im in o-
residue dissolved in H
with 1 N NaOH and then extracted with EtOAc (3 × 20 mL).
The extracts were dried (Na SO ), filtered, and concentrated
to afford essentially pure 88: H NMR (400 MHz, CDCl
2
O (10 mL). This solution was made basic
m eth yl]ph en yl]car bon yl]am in o]-2-tetr alin acetic Acid 1,1-
Dim eth yleth yl Ester (78). This compound was prepared
from 77 using the thio-Pinner sequence previously described:
2
4
1
3
) δ
3
8 1
H NMR (CDCl
3
, 400 MHz) δ 1.45 (s, 9H), 1.54 (s, 9H), 1.60
1.26 (t, J ) 7.3 Hz, 3H), 1.74 (m, 1H), 2.02 (m, 1H), 2.55 (dd,
J ) 5.8, 15.1 Hz, 1H), 2.85-2.60 (m, 3H), 4.18 (q, J ) 7.3 Hz,
2H), 4.38 (m, 1H), 6.40 (d, J ) 1.8 Hz, 1H), 6.46 (dd, J ) 1.8,
(
3
1
m, 1H), 1.95 (m, 1H), 2.22 (m, 3H), 2.41 (m, 1H), 2.80 (m,
H), 7.04 (d, J ) 8.2 Hz, 1H), 7.3 (d, J ) 8.1 Hz, 1H), 7.4 (s,
1
-
H), 7.90 (m, 4H); IR (KBr) 1718, 1667, 1613, 1527, 1286 cm
) C,H,N.
-[[[4-(Am in oim in om eth yl)p h en yl]ca r bon yl]a m in o]-2-
;
3
8.3 Hz, 1H), 6.06 (d, J ) 8.3 Hz, 1H); IR (CHCl ) 2985, 1729,
-
1
MS (FAB) m/e 508. Anal. (C29
H
37
N
3
O
5
3
1624, 1499, 1086 cm ; MS (ES) m/e 253. Anal. (C13H17NO )
C,H,N.
6
6
-[(4-Cyan oben zoyl)am in o]-2[2H]-ch r om an eacetic Acid
tetr a lin a cetic Acid Tr iflu or oa ceta te (79). This compound
was prepared from 78 using the same procedure employed for
the preparation of 8: H NMR (300 MHz, CD
H), 2.0 M, 4H), 2.21 (m, 1H), 2.39 (m, 2H) 2.45 (m, 1H), 2.90
Eth yl Ester (89). This compound was prepared from 88 and
4-cyanobenzoic acid according to the procedure outlined for
1
3
OD) δ 1.5 (m,
the preparation of 77: 1H NMR (400 MHz, CDCl
) δ 1.29 (t, J
1
(
8
1
0
3
)
7.23 Hz, 3H), 1.80 (m, 1H), 2.10 (m, 1H), 2.61 (dd, J ) 5.8,
m, 3H), 7.04 (d, J ) 7.7 Hz, 1H), 7.40 (m, 2H), 7.91 (d, J )
1
5.6 Hz, 1H), 2.80 (m, 2H), 2.95 (m, 1H), 4.20 (q, J ) 7.3 Hz,
.4 Hz, 2H), 8.12 (d, J ) 8.3 Hz, 1H); IR (KBr) 3322, 3104,
1
-
2H), 4.29 (m, 1 h), 6.79 (d, J ) 8.7 Hz, 1H), 7.20 (br d, J ) 8.7
Hz, 1H), 7.45 (s, 1H), 7.63 (s, 1H), 7.77 (d, J ) 8.3 Hz, 2H),
712, 1667, 1141 cm ; MS (FAB) m/e 352. Anal. (C22
.2H O) C,H,N.
-[[(1,1-Dim eth yleth oxy)ca r bon yl]a m in o]-3,4-d ih yd r o-
22 3 5 3
H N O F ‚
2
7
1
.94 (d, J ) 8.3 Hz, 2H); IR (KBr) 3270, 2228, 1726, 1645,
533, 1188 cm ; MS (ES) m/e 364. Anal. (C21
6
-1
H
20
N
2
O
4
2
‚0.24H O)
2
2
-oxo-2H-ben zop yr a n (86). In a 1.5-L Parr bottle, 10 g of
0% Pd/C was washed with 100 mL of anhydrous THF
C,H,N.
6
-[[[4-[[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]im in o-
overnight. After decantation of the palladium catalyst, the
THF was removed and replaced by 900 mL of anhydrous THF.
Then, 90.5 g (0.47 mol) of 6-nitrocoumarin, 155 g (0.71 mol) of
di-tert-butyl dicarbonate, and 43 g of 0.3-nm molecular sieves
were added and the reaction mixture was shaken with a Parr
apparatus at a pressure of 25 psi for 1.5 h while the temper-
ature was maintained below 60 °C. After shaking at room
temperature at a pressure of 40 psi for 24 h, 10 g of 20% Pd/
C, previously washed with THF, and 20 g of 0.3-nm molecular
sieves were added and the hydrogen pressure was maintained
for 46 h. The reaction mixture was filtered through Celite
which was then washed with 200 mL of EtOAc. The organic
layer was concentrated to dryness and the resulting solid
crystallized from 400 mL of EtOAc to afford 86 g (70%) of 86.
The filtrate was concentrated to a volume of 100 mL to afford
m e t h yl]p h e n yl]ca r b on yl]a m in o]-2[2H ]-ch r om a n e a ce -
tic Acid Eth yl Ester (90). This compound was prepared from
3
8
8
9 utilizing the thio-Pinner sequence previously disclosed:
1
H NMR (400 MHz, CDCl
3
) δ 1.28 (t, 3H), 1.53 (s, 9H), 1.75
(
3
m, 1H), 2.05 (m, 1H), 2.76 (dd, J ) 5.8, 15.6 Hz, 1H), 2.80 (m,
H), 4.19 (q, J ) 7.3 Hz, 2H), 4.25 (m, 2H), 6.75 (d, J ) 8.9
Hz, 1H), 7.23 (m, 1H), 7.47 (s, 1H), 7.73 (s, 4H), 8.35 (br s,
-
1
1
(
H); IR (CHCl
ES) m/e 481. Anal. (C26
6-[[[4-(Am in oim in om et h yl)p h en yl]ca r b on yl]a m in o]-
3
) 1729, 1660, 1613, 1528, 1497, 1286 cm ; MS
H
31
N
3
O
6
‚1.3H O) C, H, N.
2
2[2H]-ch r om a n ea cetic Acid Eth yl Ester Tr iflu or oa ceta te
(91). The title compound was prepared from 90 by reaction
with neat TFA at room temperature for 1 h followed by
concentration. The crude residue was triturated with Et
yielding a white solid which was collected by filtration:
2
1
O
H
6 g (21%) of 86 as a second crop: 1H NMR (250 MHz, CDCl
δ 7.39 (s, 1H), 7.84 (dd, J ) 10.3 Hz, 2.5 Hz, 1H), 6.98 (s, 1H),
2
3
)
NMR (400 MHz, CD
3
OD) δ 1.25 (t, J ) 7.3 Hz, 3H), 1.77 (m,
1
4
H), 2.10 (m, 1H), 2.60-3.0 (m, 4H), 4.18 (q, J ) 7.3 Hz, 2H),
.40 (m, 1H), 6.72 (d, J ) 8.7 Hz, 1H), 7.31 (m, 1H), 7.40 (m,
6
7
1
.87 (d, J ) 10 Hz, 1H), 2.90 (t, J ) 7.5 Hz, 2H), 2.70 (td, J )
.5 Hz, 2.5 Hz, 2H), 1.46 (s, 9H); IR (CDCl ) 1769, 1757, 1723,
523, 1148 cm ; MS (FD) m/e 263. Anal. (C14 ) C,H,N.
-[[(1,1-Dim eth yleth oxy)ca r bon yl]a m in o]-2[2H]-ch r o-
m a n ea cetic Acid Eth yl Ester (87). To a solution of 52.66 g
0.2 mol) of 86 in 500 mL of CH Cl under nitrogen at -78 °C
3
-
1
1H), 7.89 (d, J ) 8.3 Hz, 2H), 8.05 (d, J ) 8.3 Hz, 2H); IR
H
17NO
4
-
1
(
KBr) 3314, 3089, 1735, 1669, 1205 cm ; MS (ES) m/e 381.
Anal. (C23 ‚0.38H O) C, H, N.
-[[[4-(Am in oim in om et h yl)p h en yl]ca r b on yl]a m in o]-
[2H]-ch r om a n ea cetic Acid Tr iflu or oa ceta te (93). This
compound was prepared from 90 using the procedure outlined
for the preparation of 63: 1H NMR (400 MHz, CD
OD) δ 1.75
m, 1H), 2.10 (m, 1H), 2.60-2.84 (m, 3H), 2.90 (m, 1H), 4.42
m, 1H), 6.74 (d, J ) 8.8 Hz, 1H), 7.33 (dd, J ) 2.9, 8.7 Hz,
H), 7.41 (d, J ) 2.9 Hz, 1H), 7.92 (d, J ) 8.3 Hz, 2H), 8.13 (d,
6
H
24
N
3
O
6
F
3
2
6
(
2
2
2
was added dropwise 240 mL (0.24 mol) of a toluene solution
of 1 M DIBAH within 1 h. After the reaction mixture was
maintained at -75 °C for 1 h and then at -65 °C for 30 min,
3
(
(
1
6
0 mL of methanol and then 90 mL of water were added
dropwise. The slurry was stirred at room temperature for 2 h
and filtered through 100 g of Celite. The cake was washed four
times with 250 mL of dichloromethane. The combined organic
layers were dried over sodium sulfate and concentrated to
dryness to afford 53 g (100%) of crude reduction product. This
material was of sufficent purity for use in the next step. To a
solution of 53 g of this material in 500 mL of toluene was added
J ) 8.3 Hz, 2H); IR (KBr) 3321, 3101, 1715, 1667, 1496, 1205
cm ; MS (ES) m/e 354 (MH ). Anal. (C21
-
1
+
H
20
N
3
O
6
F
3
2
‚0.4H O)
C,H,N.
Biologica l Assa ys. 1. Solid -P h a se Liga n d Bin d in g
Assa ys. The ability of the compounds to antagonize the
7
0 g (0.2 mol) of (carbethoxymethylene)triphenylphosphorane
binding of fibrinogen to GPIIb-IIIa and vitronectin to R
v 3
â was
and the resulting solution maintained at reflux under nitrogen
for 22 h. After cooling to room temperature and evaporation
of toluene under reduced pressure, the resulting oil (125 g)
was purified by filtration on 1 kg of silica gel eluting first with
pure cyclohexane and then with cyclohexane/EtOAc (from 95:5
determined by ELISA (enzyme-linked immunoadsorbent as-
say) as previously described.5
4,55
2. P la telet Aggr ega tion Assa y. Assessment of functional
blockade of GPIIb-IIIa was made using ADP-induced platelet
aggregation in human platelet-rich plasma (PRP). Varying

4
888 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Fisher et al.
concentrations of test compound or vehicle were incubated in
(15) Nutt, R. F.; Brady, S. F.; Colton, C. D.; Sisko, J . T.; Ciccarone,
T.; Levey, M. R.; Duggan, M. E.; Imagire, I. S.; Gould, R. J .;
Anderson, P. S.; Veber, D. F. Development of Novel, Highly
Selective Fibrinogen Receptor Antagonists as Potentially Useful
Antithrombotic Agents. In Peptides: Chemistry and Biology,
Proceedings of the 12th American Peptide Symposium; Smith,
J . A., River, J . E., Eds.; ESCOM: Leiden, 1992; pp 914-916.
16) Barker, P. L.; Bullens, S.; Bunting, S.; Burdick, D. J .; Chan, K.
S.; Deisher, T.; Eigenbrot, C.; Gadek, T. R.; Gantzos, R.; Lipari,
M, T.; Muir, C. D.; Napier, M. A.; Pitti, R. M.; Padua, A.; Quan,
C.; Stanley, M.; Struble, M.; Tom, J . Y. K.; Burnier, J . P. Cyclic
RGD Analogues as Antiplatelet Antithrombotics. J . Med. Chem.
human PRP for 1 min prior to the addition of ADP (5 mM),
and the aggregation response was followed turbidometrically.56
3
. Or a l Dosin g of Com p ou n d s to Ra ts a n d Gu in ea P igs.
Animals were fasted overnight and dosed by oral gavage. The
compounds 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.
(
4
. P la sm a An a lysis P r oced u r e. Plasma (0.2 mL) was
1
992, 35, 2040-2048.
mixed with 0.8 mL of pH 1 phosphate buffer containing
internal standard and then extracted using IST Isolute C2
(
17) Ali, F. E.; Bennett, D. B.; Raul, C. R.; Elliott, J . D.; Hwand, S.-
M.; Ku, T. W.; Lago, M. A.; Nichols, A. J .; Romoff, T. T.; Shah,
D. H.; Vasko, J . A.; Wong, A. S.; Yellin, T. O.; Yuan, C.-K.;
Samanen, J . M. Conformationally Constrained Peptides and
Semipeptides Derived from RGD as Potent Inhibitors of the
Platelet Fibrinogen Receptor and Platelet Aggregation. J . Med.
Chem. 1994, 37, 769-780
18) Cheng, S.; Craig, W. S.; Mullen, D.; Tschopp, J . F.; Dixon, D.;
Pierschbacher, M. D. Design and Synthesis of Novel Cyclic RGD-
Containing Peptides as Highly Potent and Selective Integrin
(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 main-
tained at 40 °C with UV detection at 235 nm. The standard
curves for tested analogues were linear from 10 to 5120 ng/
mL.
(
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental procedures for the preparation of compounds 19, 20,
â 3
RII -â Antagonists. J . Med. Chem. 1994, 37, 1-8.
(19) J ackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.;
Higley, A.; Krywko, J .; Rockwell, A.; Markwalder, J .; Wells, G.;
Wexler, R.; Mousa, S.; Harlow, R. Template-Constrained Cyclic
Peptides: Design of High-Affinity Ligands for GPIIb/IIIa. J . Am.
Chem. Soc. 1994, 116, 3220-3230.
2
8, 37, 47, 56, 71, 84, and 94-99. This information is available
free of charge via the Internet at http://pubs.acs.org.
Refer en ces
(20) Hartman, G. D.; Egbertson, M. S.; Halczenko, W.; Laswell, W.
L.; Duggan, M. E.; Smith, R. L.; Naylor, A. M.; Manno, P. D.;
Lynch, R. J .; Zhang, G.; Cheng, C. T.-C.; Gould, R. J . Non-
Peptide Fibrinogen Receptor Antagonists. 1. Discovery and
Design of Exosite Inhibitors. J . Med. Chem. 1992, 35, 4640-
(
1) For recent reviews, see: (a) Samanen, J . Annu. Rep. Med. Chem.
1
996, 1, 91-100. (b) Ogima, I.; Chakravarty, S.; Dong, Q.
Antithrombotic Agents: From RGD to Peptide Mimetics. Bioorg.
Med. Chem. 1995, 3, 337-360.
4
642.
(
2) Colman, R. W.; Marder, V. J .; Salzman, E. W.; Hirsch, J .
Overview of hemostasis. Hemostasis Thrombosis 1993, 3-18.
3) Phillips, D. R.; Fitzgerald, L. A.; Charo, I. F.; Parise, L. V. The
Platelet Glycoprotein IIb/IIIa Complex. Ann. N. Y. Acad. Sci.
(
21) Egbertson, M. S.; Chang, C. T.-C.; Duggan, M. E.; Gould, R. J .;
Halczenko, W.; Hartman, G. D.; Laswell, W. L.; Lynch, J . J .;
Lynch R. J .; Manno, P. D.; Naylor, A. M.; Prugh, J . D.; Ramjit,
D. R.; Sitko, G. R.; Smith, R. S.; Turchi, L. M.; Zhang, G. J . Non-
Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a
Tyrosine Template as a Mimic for Arg-Gly-Asp. J . Med. Chem.
(
1
987, 509, 177-187.
(
4) Phillips, D. R.; Charo, I. F.; Parise, L. V.; Fitzgerald, L. A. The
Platelet Membrane Glycoprotein IIb/IIIa Complex. Blood 1988,
1
994, 34, 2537-2551.
7
1, 831-843.
(
22) Duggan, M. E.; Naylor-Olsen, A. M.; Perkins, J . J .; Anderson,
P. S.; Chang, C. T.-C.; Cook, J . J .; Gould, R. J .; Ihle, N. C.;
Hartman, G. D.; Lynch, J . J .; Lynch, R. J .; Manno, P. D.;
Schaffer, L. W.; Smith, R. L. Non-Peptide Fibrinogen Receptor
Antagonists. 7. Design and Synthesis of a Potent, Orally Active
Fibrinogen Receptor Antagonist. J . Med. Chem. 1995, 38, 3332-
(
5) Phillips, D. R.; Charo, I. F.; Scarborough, R. M. GPIIb-IIIa: The
Responsive Integrin. Cell 1991, 65, 359-362.
6) Pytela, R.; Pierschbacher, M. D.; Ginsberg, M. H.; Plow, E. F.;
Rouslahti, E. Platelet Membrane Glycoprotein IIb/IIIa: Member
of a Family of Arg-Gly-Asp-Specific Adhesion Receptors. Science
(
1
986, 231, 1559-1562.
3
341.
(
7) Hawiger, J .; Kloczewiak, M.; Bednarek, M. A.; Timmons, S.
Platelet Receptor Recognition Domains on the R Chain of Human
Fibrinogen: Structure-Function Analysis. Biochemisry 1989,
(
23) Klein, S. I.; Molino, B. F.; Czekaj, M.; Dener, J . S.; Leadley, R.
J .; Sabatino, R.; Dunwiddie, C. T.; Chu, V. Non-Peptide Fibrino-
gen Receptor Antagonist Based Upon a 4-Substituted Piperidine
Scaffold. Bioorg. Med. Chem. Lett. 1996, 6, 1403-1408.
24) Alig, L.; Edenhofer, A.; Hadvary, P.; Hurzeler, M.; Knopp, D.;
Muller, T.; Steiner, B.; Trzeciak, A.; Weller, T. Low Molecular
Weight, Non-Peptide Fibrinogen Receptor Antagonists. J . Med.
Chem. 1992, 35, 4393-4407.
25) Stilz, H. U.; J ablonka, B.; J ust, M.; Knolle, J .; Paulus, E. F.;
Zoller, G. Discovery of an Orally Active Non-Peptide Fibrinogen
Receptor Antagonist. J . Med. Chem. 1996, 39, 2118-2122.
26) Eldred, C. P.; Evans, B.; Hindley, S.; J udkins, B. D.; Kelly, H.
A.; Kitchin, J .; Lumley, B. D.; Porter, B.; Ross, B. C.; Smith, K.
J .; Taylor, N. R.; Wheatcroft, J . R. Orally Active Non-Peptide
Fibrinogen Receptor (GPIIb/IIIa) Antagonists: Identification of
2
8, 2909-2914.
(
8) Bennett, J . S.; Shattil, S. J .; Power, S. W.; Gartner, T. K.
Interaction of Fibrinogen with Its Platelet Receptor. J . Biol.
Chem. 1988, 263, 12948-12953.
(
(
9) Steiner, B.; Cousot, D.; Trzeciak, A.; Gillessen, D.; Hadvary, P.
2
+
Ca
dependent Binding of a Synthetic Arg-Gly-Asp (RGD)
(
Peptide to a Single Site on the Purified Platelet Glycoprotein
IIb-IIIa complex. J . Biol. Chem. 1989, 264, 13102-13108.
(
10) For a review and leading references, see: (a) Nichols, A. J .;
Ruffolo, R. R., J r.; Huffman, W. F.; Proste, G.; Samanen, J .
Trends Pharmacol. Sci. 1992, 13, 413. (b) Shebuski, R. J . Annu.
Rep. Med. Chem. 1991, 26, 93.
(
(
11) Samanen, J .; Ali, F. E.; Romoff, T.; Calvo, R.; Sorenson, E.;
Bennett, D.; Berry, D.; Koster, P.; Vasko, J .; Powers, D.; Stadel,
J .; Nichols, A. Reinstatement of High Receptor Affinity in a
Peptide Fragment (RGDS) Through Conformational Constraints.
In Peptides 1990, Proceedings of the 21st European Peptide
Symposium; Giralt, E., Andreu, D., Eds.; ESCOM Science
Publishers: Leiden, 1990; pp 781-783.
12) Samanen, J .; Ali, F.; Romoff, T.; Calvo, R.; Sorenson, E.; Vasko,
J .; Storer, B.; Berry, D.; Bennett, D.; Stroksacker, M.; Powers,
D.; Stadel, J .; Nichols, A. Development of a Small RGD Peptide
Fibrinogen Receptor Antagonist with Potent Antiaggregatory
Activity in Vitro. J . Med. Chem. 1991, 34, 3114-3125.
13) Nutt, R. F.; Brady, S. F.; Sisko, J . T.; Ciccarone, T. M.; Colton,
C. D.; Levy, M. R.; Gould, R. J .; Shang, G.; Friedman, P. A.;
Veber, D. F. Structure and Conformation-Activity Studies Lead-
ing to Potent Fibrinogen Receptor Antagonists Containing Arg-
Gly-Asp. In Peptides 1990; Giralt, E., Andreu, D., Eds.; ESCOM
Science Publishers B.V.: Leiden, 1991; pp 784-784.
14) Ali, F. E.; Samanen, J . M.; Calvo, R.; Romoff, T.; Yellin, T.;
Vasko, J .; Powers, D.; Stadel, J .; Bennett, D.; Berry, D.; Nichols,
A. Potent Fibrinogen Receptor Antagonists Bearing Conforma-
tional Constraints. In Peptides, Chemistry and Biology, Proceed-
ings of the 12th American Peptide Symposium; Smith, J . A.,
Rivier, J . E., Eds.; ESCOM: Leiden, 1992; pp 761-762.
4
-[4-[4-(Aminoimino-methyl)Phenyl]-1-Piperazinyl-1-Piperidineace-
tic acid as a Long-Acting, Broad-Spectrum Antithrombotic Agent.
J . Med. Chem. 1994, 37, 3882-3885.
(
27) Zablocki, J . A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretz-
man, L.; Rao, S. N.; Lindmark,.J .; Panzer-Knodle, S. G.; Nichol-
son, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Champion,
J . B.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of
Platelet Aggregation Based Upon the Arg-Gly-Asp-Phe Sequence
of Fibrinogen. A Proposal on the Nature of the Binding Interac-
tion Between the Arg Guanidine of RGDX mimetics and the
Platelet GPIIb-IIIa receptor. J . Med. Chem. 1993, 36, 1811-
1819.
(
(
(28) Zablocki, J . A.; Miyano, M.; Rao, S. N.; Panzer-Knodle, S.;
Nicholson, N.; Feigen, L. Potent Inhibitors of Platelet Aggrega-
tion Based Upon the Arg-Gly-Asp-Phe Sequence of Fibrinogen.
A Proposal on the Nature of the Binding Interaction Between
the Asp Carboxylate of RGDX mimetics and the Platelet GPIIb-
IIIa receptor. J . Med. Chem. 1992, 35, 4914-4917.
(29) Ku, T. W.; Ali, F. E. Barton, L. S.; Bean, J . W.; Bondinell, W.
E.; Burgess, J . L.; Callahan, J . F.; Calvo, R. R.; Chen, L.;
Eggelston, D. S.; Gleason, J . G.; Huffman, W. F.; Hwang, S. M.;
J akas, D. R.; Karash, C. B.; Keenan, R. M.; Kopple, K. D.; Miller,
W. H.; Newlander, K. A.; Nichols, A.; Parker, M. F.; Peischoff,
(

Fused Bicyclic Gly-Asp â-Turn Mimics
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4889
C. E.; Samanen, J . M.; Uzinskas, I.; Venslavsky, J . W. Direct
Design of a Potent Non-Peptide Fibrinogen Receptor Antagonist
Based on the Structure and Conformation of a Highly Con-
strained Cyclic RGD Peptide. J . Am. Chem. Soc. 1993, 115,
(42) Shtacher, G.; Erez, M.; Cohen, S. Selectivity in new â-Adrenergic
Blocking Agents. (3-Amino-2-hydroxypropoxy)benzamides. J .
Med. Chem. 1973, 16, 516-519.
(43) Schnur, R. C.; Howard, H. R. 1,2,3,4-Tetrasubstituted isoquino-
lineacetic acids. Tetrahedron Lett. 1981, 22, 2843-2846.
(44) Bryson, T. A. Lactomethylation of Activated Aromatic Carboxylic
Acids. Synth. Commun. 1973, 3, 173-175.
8
861-8862.
(
30) Callahan, J . F.; Bean, J . W.; Burgess, J . L.; Eggelston, D. S.;
Hwang, S. M.; Kopple, K. D.; Koster, P.f.; Nichols, A.; Peishoff,
C. E.; Samanen, J . M.; Vasko, J . A.; Wong, A.;. Huffman, W. F.
(
45) Cignarella, G.; Barlaocco, D.; Pinna, G. A.; Loriga, M.; Curzu,
M. M.; Tofanetti, O.; Germini, M.; Cazzulani, P.; Cavalletti, E.
Synthesis and Biological Evaluation of Substituted Benzo[H]-
cinnolinones and 3H-Benzo[6,7]cyclohepta[1,2-c]pyridazinones;
Higher Homologues of the Antihypertensive and Antithrombotic
7
Design and Synthesis of a C Mimetic for the Predicted γ-Turn
Conformation Found in Several Constrained RGD Antagonists.
J . Med. Chem. 1992, 35, 3970-3972.
(
(
(
31) Egbertson, M. S.; Naylor, A. M.; Hartman, G. D.; Cook, J . J .;
Gould, R. J .; Holahan, M. A.; Lynch, J r., J . J .; Lynch, R. J .;
Stranieri, M. T.; Vassallo, L. M. Non-Peptide Fibrinogen Recep-
tor Antagonists. 3. Design and Discovery of a Centrally Con-
strained Inhibitor. Biorg. Med. Chem. Lett. 1994, 4, 1835-1840.
32) Hirschmann, R.; Sprengeler, P. A.; Kawasaki, T.; Leahy, J . W.;
Shakespeare, W. C.; Smith, A. B., III. The First Design and
Synthesis of a Steroidal Peptidomimetic. The Potential Value
of Peptidomimetics in Elucidating the Bioactive Conformation
of Peptide Ligands. J . Am. Chem. Soc. 1992, 114, 9699-9701.
33) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.;
Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.;
Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. From
Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-
Peptidal Inhibitors of Platelet Aggregation Based on a Benzo-
diazepinedione Scaffold. J . Am. Chem. Soc. 1994, 116, 5077-
5
2
H-Indeno[1,2-c]pyridazinones. J . Med. Chem. 1989, 32, 2277-
282.
(
(
46) Cohen, N.; Weber, G. F. Eur. Pat. Appl., EP 129906 A1.
47) (a) Mousa, S. A.; Forsythe, M.; Lorelli, W.; Bozarth, J .; Xue, C.
B.; Wityak, J .; Sielecki, T. M.; Olson, R. E.; DeGrado, W.; Kapil,
R.; Hussain, M.; Wexler, R.; Thoolen, M. J .; Reilly, T. M. Novel
nonpeptide antiplatelet glycoprotein IIb/IIIa receptor antagonist,
DMP754: receptor binding affinity and specificity. Cor. Art. Dis.
1
996, 7, 767-74. (b) Guth, B. D.; Seewaldt-Becker, E.; Him-
melsbach, F.; Weisenberger, H.; Muller, T. H. Antagonism of the
GPIIb/IIIa receptor with the nonpeptidic molecule BIBU52:
inhibition of platelet aggregation in vitro and antithrombotic
efficacy in vivo. J . Cardiovasc. Pharmacol. 1997, 30, 261-72.
48) Hutchinson, J . H.; Cook, J . J .; Brashear, K. M.; Breslin, M. J .;
Glass, J . D.; Gould, R. J .; Halczenko, W.; Holahan, M. A.; Lynch,
R. J .; Sitko, G. R.; Stranieri, M. T.; Hartman, G. D. Non-Peptide
Glycoprotein IIb/IIIa Antagonists. 11. Design and in vivo Evalu-
ation of 3,4-Dihydro-1-(1H)-isoquinolinone-Based Antagonists.
J . Med. Chem. 1996, 39, 4583-4591.
(
5
083.
(
34) Miller, W. H.; Ali, F. E.; Bondinell, W. E.; Callahan, J . F.; Calvo,
R. R.; Eggleston, D. S.; Haltiwanger, R. C.; Huffman, W. F.;
Hwang, S.-M.; J akas, D. R.; Keenan, R. M.; Koster, P. F.; Ku,
T. W.; Kwon, C.; Newlander, K. A.; Nichols, A. J .; Parker, M,
F.; Samanen, J . M.; Southall, L. S.; Takata, D. T.; Uzinskas, I.
N.; Valocik, R. E.; Vasko-Moser, J . A.; Wong, A. S.; Yellin, T.
O.; Yuan, C. C. K. Structure-Activity Relationships in 3-Oxo-
(49) Ku, T. W.; Miller, W. H.; Bondinell, W. E.; Erhard, K. F.; Keenan,
R. M.; Nichols, A. J .; Peishoff, C. E.; Samanen, J . M.; Wong, A.
S.; Huffman, W. F. Potent Non-Peptide Fibrinogen Receptor
Antagonists Which Present an Alternative Pharmacophore. J .
Med. Chem. 1995, 38, 9-12.
(50) Keenan, R. M.; Miller, W. H.; Kwon, C.; Ali, F. E.; Callahan, J .
F.; Calvo, R. R.; Hwang, S.-M.; Kopple, K. D.; Peishoff, C. E.;
Samanen, J . M.; Wong, A. S.; Yuan, C.-K.; Huffman, W. F.;
1
2
2
,4-Benzodiazepine-2-Acetic Acid GPIIb/IIIa Antagonists. The
-Benzazepine Series. Bioorg. Med. Chem. Lett. 1996, 6, 2481-
486.
(
35) Egbertson, M. S.; Hartman, G. D.; Gould, R. J .; Bednar, B.;
Bednar, R. A.; Cook, J . J . Gaul, S. L.; Holahan, M. A.; Libby, L.
A.; Lynch, J . J .; Lynch, R. J .; Sitko, G. R.; Stranieri, M. T.;
Vassallo, L. M. Nonpeptide GPIIb/IIIa Inhibitors. 10. Centrally
Constrained Alpha-Sulfonamides are Potent Inhibitor of Platelet
Aggregation. Bioorg. Med. Chem. Lett. 1996, 6, 2519-2524.
36) Wityak, J .; Sielecki, T. M.; Pinto, D. J .; Emmett, G.; Sze, J . Y.;
Liu, J .; Tobin, E. Wang, S.; J iang, B.; Ma, P.; Mousa, S. A.;
Wexler, R. R.; Olson, R. Discovery of Potent Isoxazoline Glyco-
protein IIb/IIIa Receptor Antagonists. J . Med. Chem. 1997, 40,
Discovery of Potent Nonpeptide Vitronectin Receptor (R
Antagonists. J . Med. Chem. 1997, 2289-2292.
v 3
â )
(
51) The identity of the arginine isostere has also been shown to play
an influential role in the determination of integrin selectivity.
For leading references, see: Keenan, R. M.; Miller, W. H.; Lago,
M. A.; Ali, F. E.; Bondinell, W. E.; Callahan, J . F.; Calvo, R. R.;
Cousins, R. D.; Hwang, S.-M.; J akas, D. R.; Ku, T. W.; Kwon,
C.; Nguyen, T. T.; Reader, V. A.; Rieman, D. J .; Ross, S. T.;
Takata, D. T.; Uzinskas, I. N.; Yuan, C. C. K.; Smith, B. R.
Bioorg. Med. Chem. Lett. 1998, 3165-3170.
(
(
(
5
0-60.
37) Fisher M. J .; Gunn, B. P.; Harms, C. S.; Kline, A. D.; Mullaney,
J . T.; Scarborough, R. M.; Skelton, M. A.; Um, S. L.; Utterback,
B. G.; J akubowski, J . A. Dihydro-isoquinolone RGD Mimics.
Exploration of the Aspartate Isostere. Bioorg. Med. Chem. Lett.
(
(
(
52) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley and Sons, Inc.: New York, 1967; p 584.
53) Tomita, M.; Minami, S.; Uyeo, S. Schmidt reaction with Benzo-
cycloalkenones. J . Chem. Soc. C 1969, 183-188.
1
997, 7, 2537-2542.
38) Fisher, M. J .; Gunn, B.; Harms, C. S.; Kline, A. D.; Mullaney, J .
T.; Nunes, A.; Scarborough, R. M.; Skelton, M. A.; Um, S. L.;
Utterback, B. G.; J akubowski, J . A. Non-Peptide RGD Sur-
rogates Which Mimic a Gly-Asp Beta-Turn are Potent Antago-
nists of Platelet Glycoprotein IIb-IIIa. J . Med. Chem. 1997, 40,
54) Scarborough, R. M.; Rose, J . W.; Naughton, M. A.; Phillips, D.
R.; Nannizzi, L.; Arfsten, A.; Campbell, A. M.; Charo, I. F.
Characterization of the integrin specificities of disintegrins
isolated from American pit viper venoms. J . Biol. Chem. 1993,
2
68, 1058-1065.
2
085-2101.
(
39) Scarborough, R. M.; Naughton M. A.; Teng, W.; Rose, J . W.;
Phillips, D. R.; Nannizzi, L.; Arfsten, A.; Campbell, A. M.; Charo,
I. F. Design of Potent and Specific Integrin Antagonists. J . Biol.
Chem. 1993, 268, 1066-1073.
40) Similar compounds have recently been reported in the litera-
ture: Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.;
Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.
New Platelet Fibrinogen Receptor Glycoprotein IIb-IIIa Antago-
nists: Orally Active Series of N-Alkylated Amidines with a 6,6-
Bicyclic Template. J . Med. Chem. 1998, 41, 4036-4052.
41) Hennige, H.; Kreher, R. P.; Konrad, M.; J elitto, F. Studies on
the Chemistry of Isoindoles and Isoindolenines. Chem. Ber. 1988,
(55) Su, T.; Naughton, A. H.; Smyth, M. S.; Rose, J . W.; Arfsten, A.
E.; McCowan, J . R.; J akubowski, J . A.; Wyss, V. L.; Ruterbories,
K. J .; Sall, D. J .; Scarborough, R. M. Fibrinogen receptor (GPIIb-
IIIa) antagonists derived from 5,6-bicyclic templates. Amidi-
noindoles, amidinoindazoles and amidinobenzofurans containing
the N-R-sulfonamide carboxylic acid function as potent platelet
aggregation inhibitors. J . Med. Chem. 1997, 40, 4308-4318.
(56) J akubowski, J . A.; Maraganore, J . M. Inhibition of coagulation
and thrombin-induced platelet activities by a synthetic dode-
capeptide modeled on the carboxy terminus of hirudin. Blood
1990, 75, 399-406.
(
(
1
21, 243-252.
J M990365Y