RGD mimetics containing a central hydantoin scaffold: α(v)β3 vs α(IIb)β3 selectivity requirements

Article abstract of DOI:10.1016/S0960-894X(99)00661-7

The synthesis of a series of RGD mimetic α(v)β₃ antagonists containing a hydantoin scaffold is shown. The results demonstrate some of the structural requirements for the design of selective α(v)β₃ antagonists (vs α(IIb)β₃)

Full text of DOI:10.1016/S0960-894X(99)00661-7

Bioorganic & Medicinal Chemistry Letters 10 (2000) 179±182
RGD Mimetics Containing a Central Hydantoin Sca€old:
ꢀVꢁ3 vs ꢀIIbꢁ3 Selectivity Requirements
Anusch Peyman, a,* Volkmar Wehner, a Jochen Knolle, a Hans Ulrich Stilz, a
Gerhard Breipohl, a Karl-Heinz Scheunemann, a Denis Carniato, b Jean-Marie Ruxer, b
Jean-Francois Gourvest, b Thomas R. Gadek c and Sarah Bodary c
aHoechst Marion Roussel Deutschland GmbH, D-65926 Frankfurt, Germany
b
Â
Hoechst Marion Roussel, 102 Route de Noisy, 93235 Romainville Cedex, France
cGenentech, 1 DNA Way, South San Francisco, CA 94080, USA
Received 8 September 1999; accepted 22 November 1999
AbstractÐThe synthesis of a series of RGD mimetic aVb3 antagonists containing a hydantoin sca€old is shown. The results
demonstrate some of the structural requirements for the design of selective aVb3 antagonists (vs aIIbb3) in terms of the Arg-mimetic,
the distance between N- and C-terminus and the lipophilic side chain. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
the discovery of an orally active non-peptide ®brinogen
receptor antagonist containing a hydantoin sca€old.22
Here we present structural requirements that determine
the selectivity of an RGD mimetic with such a central
hydantoin building block towards aIIbb3 and aVb3. In
particular we investigated the in¯uence of the arginine
mimetic, the distance between N- and C-terminus and
the lipophilic side chain.
Integrins are a widely expressed family of a/b hetero-
dimeric cell surface receptors which bind to extracellular
matrix adhesive proteins such as ®brinogen, ®bronectin,
vitronectin, laminin, osteopontin etc.1±3 Currently
integrins are known to be composed of a±b dimers of
the existing ®fteen a subunits and the eight b subunits.
The b3 class of the integrin family, aIIbb3 (also known as
GPIIb/IIIa or ®brinogen receptor) and aVb3 (vitro-
nectin receptor), has received special attention in recent
drug discovery e€orts.4,5 aIIbb3 is prevalent on platelets
and plays a role in thromboembolic disorders.5,6 aVb3 is
the dominant receptor for mediating the attachment of
osteoclasts to bone during bone resorption7,8 and has
been implicated in tumor progression, angiogenesis5,9
and restenosis.10 Many integrins, including aIIbb3 and
aVb3, interact with a common Arg-Gly-Asp (RGD)
binding motif in their target proteins.11±13 For drug
development it is highly desirable to obtain integrin
antagonists which bind selectively to speci®c integrins.
Using stereoisomeric cyclic peptide libraries, Kessler
et al. were able to pinpoint the structural properties
needed for the selective inhibition of either aIIbb3 or
aVb3.14,15 Other selective peptidomimetic inhibitors of
aVb3 have been reported recently.16±21 Earlier we reported
Synthesis
The synthesis of antagonist 7 is outlined in Scheme 1.
The central step is the formation of the hydantoin
building block 4, which is converted to the guanidine 5
using 1H-Pyrazole-1-carbox-amidine.23 Compound 5 is
then coupled with the 2S-(benzyloxycarbonylamino)-3-
aminopropionic acid tert-butylester to give 6. Depro-
tection with TFA provides the antagonist 7. The
antagonists 8 and 10 are prepared analogously with
starting materials containing di€erent chain lengths.
The antagonist 9 is prepared starting from Arg-OMe
which is reacted with isocyanatoacetic acid methylester
in analogy to Scheme 1 to form the corresponding
hydantoin, followed by the hydrolysis of the methyl-
ester, coupling with 2S-(benzyloxycarbonylamino)-3-
aminopropionic acid tert-butylester and TFA cleavage
of the tert-butylester. Compounds 11 and 12 (Table 2)
are prepared by treatment of 4 (n=3) with 2-methylthio-
2-imidazoline, or by reaction with 2-bromopyrimidine
*Corresponding author. Fax: +49-69-305-80679; e-mail: anusch.
peyman@hmrag.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00661-7

180
A. Peyman et al. / Bioorg. Med. Chem. Lett. 10 (2000) 179±182
Scheme 1. Synthesis of integrin antagonists 7±10.
respectively, followed in each case by the last two
synthesis steps from Scheme 1.
and coupling of the appropriate side chain to the free
amino function.
Scheme 2 shows the synthesis of antagonist 16 which
carries a N-terminal amino-benzimidazole group. It
starts with building block 4 (n=3) which is reacted with
2-nitrophenylisothiocyanate followed by reduction of
the nitro group and cyclization using mercury oxide and
sulfur to give 15. Compound 15 is then reacted further
as in Scheme 1 to give antagonist 16.
The IC50 values for the inhibition of ®brinogen to aIIbb3
and of Kistrin (a disintegrin with high anity for
aVb38,24) to aVb3 are summarized in Tables 1±3. Table 1
shows the in¯uence of spacer length on the aIIbb3/aVb3
selectivity. The optimum distance for an aVb3 antagonist
seems to be 12 bonds between the C-terminal carboxyl
group and the N-terminal guanidino group (compound
9), while for aIIbb3 a distance of 13 (or more) bonds
results in higher anity (compound 10). This observa-
tion is in good agreement with the results obtained for
other inhibitors16,17 and with Kessler's observation
that in cyclopeptides the aVb3-selective molecules are
strongly bent, while aIIbb3-selective molecules are in a
more extended conformation.14 The in¯uence of the
arginine mimetic on the aIIbb3/aVb3 selectivity is shown
in Table 2. The comparison of 9 with 11 or 16 illustrates
that for aVb3 selectivity cyclic guanidines are preferred
over non cyclic guanidines. The incorporation of cyclic
guanidines also leads to decreased anity for aIIbb3.
Scheme 3 shows the synthesis of antagonists 23 starting
with the hydantoin 18 formation from l-aspartic acid,
followed by esteri®cation and alkylation with tert-
butylbromoacetate to give 20, and successive coupling
with 2S-(benzyloxycarbonylamino)-3-aminopropionic
acid tert-butylester and 2-aminomethylbenzimidazole.
Finally, treatment with TFA gave 23. Antagonist 24
was obtained in the same way using (4,5-dihydro-
imidazol-2-yl)-hydrazine instead of 2-aminomethyl-
benzimidazole. Compounds 25±29 were obtained by
catalytic hydrogenation of 9 to remove the Cbz group
Scheme 2. Synthesis of benzimidazole containing integrin antagonist 16.

A. Peyman et al. / Bioorg. Med. Chem. Lett. 10 (2000) 179±182
181
Scheme 3. Synthesis of benzimidazole containing integrin antagonist 23.
Table 1. In¯uence of spacer length on aIIbb3/aVb3 selectivity. The
IC50 values denote the concentration required to reduce binding of
®brinogen (Fg) to aIIbb3 or of Kistrin (K) to aVb3 by 50%
Table 2. In¯uence of arginine mimetic on aIIbb3/aVb3 selectivity
R1
Fg/aIIbb3 IC50 (mM) K/aVb3 IC50 (mM)
9
2.4
0.08
n
Fg/aIIbb3 IC50 (mM)
K/aVb3 IC50 (mM)
11
>10
0.02
7
8
9
10
1
2
3
4
10
10
2.4
0.85
15
5
0.08
0.2
12
16
23
>10
>10
5
1.66
0.04
15
One could speculate that the antagonists bind to aIIbb3
through an ``end-on'' interaction, while aVb3-binding is
achieved through ``side-on'' binding.
24
>10
0.58
For aVb3 binding the guanidino N-terminus is clearly
preferred over the aminopyrimidino terminus (com-
pound 12). The guanidino-type 2-aminobenzimidazole
(compound 16) is more than 100-fold more active than
the corresponding (non-guanidino) aminomethylbenz-
imidazole derivative 23. Table 3 shows the in¯uence of
the lipophilic side chain on aIIbb3/aVb3 selectivity,
wherein the carbamate containing antagonist 9 exhibits
by far the highest activity and selectivity for aVb3. The
thiourea containing compound 27 has the lowest anity
both for aVb3 and aIIbb3, while all other side chains (25,
26, 28, 29) give almost comparable results. This work
demonstrates the versatility of the hydantoin sca€old
and the structural requirements in the design of selective
aVb3 antagonists in terms of the arginine mimetic, the

182
A. Peyman et al. / Bioorg. Med. Chem. Lett. 10 (2000) 179±182
Table 3. In¯uence of side chain on aIIbb3/aVb3 selectivity
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