Discovery of an orally active non-peptide fibrinogen receptor antagonist

Full text of DOI:10.1021/jm960210f

2118
J . Med. Chem. 1996, 39, 2118-2122
Communications to the Editor
diastereomeric mixture 3 showed an IC50 of 40 nM.
The methyl group was introduced into the structure
of 3 at the 4 position of the hydantoin ring in order
to allow the isolation of individual stereoisomers
since a hydrogen at the same position has proven to be
acidic, thus preventing isolation of individual stereoi-
somers.23
Discover y of a n Or a lly Active
Non -P ep tid e F ibr in ogen Recep tor
An ta gon ist
Hans Ulrich Stilz,*,† Bernd J ablonka,‡ Melitta J ust,‡
J ochen Knolle,† Erich Friedrich Paulus,† and
Gerhard Zoller‡
Compound 3 provides a potent platelet aggregation
inhibitor in vitro. Unfortunately, however, this first
generation inhibitor showed only a limited bioavailabil-
ity. In order to improve oral activity of respective
molecules we modified the carboxyl terminus with the
intention to reduce the number of polar functional
groups and to lower the molecular weight of compounds.
A novel series of potent platelet aggregation inhibitors
was finally discovered by replacing the carboxyl-
terminal Asp-Phg moiety of 3 by various â-amino acid
derivatives (Table 2). Interestingly, orally active fi-
brinogen receptor antagonists based on quite different
scaffolds where a â-amino acid derivative was incorpo-
rated at the carboxy terminus of the molecules have
been reported by other research groups as well.17d,20a
The phenyl ring of the â-amino acid appears to be
important for the activity of 4. Replacement of the
phenyl ring by an alkyl side chain in 8 decreased
potency in vitro. Exchange of the phenyl ring by the
larger naphthyl ring in 7 apparently slightly decreased
potency in vitro. Changing the electron density of the
aromatic side chain in compounds 5 and 6 slightly
improved the in vitro potency.
Central Pharma Research and TD Cardiovascular Agents,
Hoechst AG, D-65926 Frankfurt am Main, Germany
Received March 14, 1996
Arterial thromboembolic events and their ischemic
complications give rise to a variety of vasoocclusive
disorders such as unstable angina, myocardial infarc-
tion, stroke, or peripheral arterial disease.1-3 The acute
vascular occlusion is caused by deposition and aggrega-
tion of platelets on thrombogenic surfaces such as
ruptured atherosclerotic plaques leading to platelet-rich
thrombus formation at the site of injury.4 Fibrinogen
binding to a platelet membrane glycoprotein, the inte-
grin GP IIb/IIIa, is recognized as the final common
pathway of platelet aggregation through cross-linking
of adjacent platelets. Antagonists of GP IIb/IIIa are
therefore expected to be a new promising class of
antithrombotic agents offering potential advantages
over present antiplatelet agents including aspirin and
ticlopidine, which only interfere with one single ago-
nistic pathway.5
Platelet GPIIb/IIIa antagonists reported to date in-
clude monoclonal antibodies,6,7 polypeptides from snake
venoms8 and leeches,9 linear and cyclic peptides
containing either the arginine-glycine-aspartic acid
(RGD) recognition sequence10-14 or the carboxyl-termi-
nal sequence from the fibrinogen γ-chain,15 and non-
peptide antagonists.5,16-21 Many of these compounds
have been shown to inhibit platelet aggregation
independent of the activating agonist, as well as to
prevent thrombus formation in animal models or in
humans.5,12b,16,17a,b,19,20,22 In this communication, we
report the discovery of a new potent, orally active non-
peptide GPIIb/IIIa antagonist, which mimics the RGD
recognition sequence.
The Arg-Gly-Asp-Ser tetrapeptide was used as an
initial lead compound. Our goal was to convert the only
modestly active tetrapeptide inhibitor (IC50 ) 100 µM
for the inhibition of ADP-mediated platelet aggregation)
into a potent, metabolically stable, and orally active
GPIIb/IIIa antagonist (Table 1). In a first step we
conformationally constrained the linear peptide by
introducing a hydantoin ring. The resulting compound
1 showed an improved potency by a factor of 10.
Another factor of 10 in potency was gained by replacing
the serine residue by a phenylglycine in compound 2.
As has been observed by others as well,5,12b,15 a dramatic
increase in potency was obtained by replacing the
flexible arginine side chain by a benzamidine. The
Platelet aggregation inhibitor 4 was found to be orally
active in conscious dogs. Oral bioavailability after iv
and oral administration of 4 was determined to be 5%
(n ) 2) by bioassay using isolated and immobilised
GPIIb/IIIa.25 The ethyl ester prodrug of 4 showed a
bioavailability in conscious dogs of 55 ( 7% (n ) 2). This
encouraging result prompted us to synthesize all four
individual stereoisomers of the diastereomeric mixture
4. The synthesis is outlined in Scheme 1 for one
particular stereoisomer. Briefly, ethyl (S)-2-amino-2-
(4-bromophenyl)propionate (11) was obtained by sepa-
ration of the racemate with (R)-mandelic acid as con-
firmed by X-ray analysis. The (S)-amino acid ester was
converted to hydantoin 13 by standard methods. Cou-
pling of 13 with (S)-3-amino-3-phenylpropionic acid
ethyl ester, which was prepared by chain elongation
starting from (R)-phenylglycine (Figure 8, Supporting
Information), and subsequent ester cleavage provided
15 (S 1197) as the hydrochloride salt. In the same way
all four stereoisomers were prepared and in vitro
activity was assessed (Table 3). Only stereoisomer 15
proved to be a very potent platelet aggregation inhibitor.
Compound 15 inhibited dose-dependently and revers-
ibly human and dog platelet aggregation in gel-filtered
platelets (GFP), platelet rich plasma, and whole blood
independent from the agonist used with IC50 values
between 20 and 100 nM in the different systems. In
addition, 15 inhibited 125I-fibrinogen binding to ADP-
activated human GFP24 and isolated GPIIb/IIIa25 in a
concentration dependent manner with Ki values of 9 and
* To whom correspondence should be addressed. Tel: (011-49-69)-
305-17863. FAX: (011-49-69)331399.
† Central Pharma Research.
‡ TD Cardiovascular Agents.
S0022-2623(96)00210-5 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11 2119
Ta ble 1. First-Generation Platelet Aggregation Inhibitors
a
Human platelets were isolated from platelet rich plasma (PRP) by gel filtration on Sepharose 2 B. The resulting suspension of gel-
filtered platelets (GFP) containing 3 × 108 platelets/mL was activated with 10 µM ADP in the presence of 1 mg/mL fibrinogen and stirred
at 1000 rpm at 37 °C in an aggregometer (PAP 4, Biodata, Hatboro, PA). Aggregation was measured as the maximal increase in light
transmittance. Compounds were added to GFP at 37 °C 2 min before the activation with ADP. Inhibition of aggregation was expressed
as IC50 value, i.e. the mean concentration requiring 50% inhibition in GFP samples of two to six different donors.
Sch em e 1a
(a) KCN, (NH4)2CO3, H2O/ethanol, 60 °C;28 (b) NaOH, 10 bar, 130 °C;28 (c) HCl, ethanol, reflux; (d) (R)-mandelic acid, 2-propanol/
MTB-ether, recrystallized; (e) (ethoxycarbonyl)methyl isocyanate, ethyl acetate; (f) HCl, reflux; (g) CuCN, DMF;29 (h) HCl, ethanol, 0
°C;30 (i) NH3, 2-propanol;30 (j) HCl, reflux; (k) (S)-3-amino-3-phenylpropionic acid ethyl ester, DCC, HOBt, DMF; (l) 6 N HCl.
0.17 nM, respectively, suggesting that 15 was a specific
inhibitor of GPIIb/IIIa-mediated platelet aggregation.
Compound 15 did not affect ristocetin-induced von
Willebrand factor binding to GPIb-IX26 or vitronectin
binding to integrin Rvâ3,25 indicating specificity of 15
toward GPIIb/IIIa (data not shown).
In conscious dogs, oral bioavailability after iv and oral
administration of 15 was determined to be 10% (n ) 4)
by bioassay. The ethyl ester prodrug 14 (S 5740;
Scheme 1) of 15 showed an even higher bioavailability.
Availability in conscious dogs was 42 ( 8% (n ) 4) and
plasma half-life was 9.9 h (Figure 1). Compound 14
(Figure 7 in Supporting Information) and the respective
hydrochloride salt S 176227 are highly effective in
preventing thrombus formation in a dog model of
coronary thrombosis (Folts model).
In conclusion, 15 is a highly potent, competitive
fibrinogen receptor antagonist. The respective ethyl
ester prodrug 14 is an antithrombotic compound with
sufficient oral availability in dogs which suggests that
it may have potential for chronic treatment and pro-
phylaxis of thrombotic diseases in humans.

2120 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11
Ta ble 2. Modification of 3 at the Carboxy Terminus
Communications to the Editor
Ta ble 3. Stereoisomers of 4

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11 2121
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