2014
A.Peyman et al./ Bioorg.Med.Chem.Lett.11 (2001) 2011–2015
from various examples 19–21 or 13–16. Considering
that the cyclopropyl-containing antagonists consist of
diastereomeric mixtures, one may speculate that one of
the pure forms could show some advantages over the
open chain ethylene spacer.
porated in the ‘C-terminus’ of RGD peptidomimetics.
On the other hand, this series shows excellent selectiv-
ities versus aIIbb3. Bulky aromatic side chains are pre-
ferred; see, for example, the increase in potency from 22
to 25. However, ortho substitution of the aromatic side
chain, as in 32 containing the 1-naphthyl group, does
not seem to enhance potency. The SAR for the spacer
and the guanidino group are the same as in the other
series. Two different side chains, benzyl and 1-ada-
mantylmethyl, were incorporated in the carbamate ser-
ies. The bulky adamantyl moiety offers a slight
advantage over the flat benzyl group, enhancing
potency by a factor of 2 (cf. 13 and 19) when used in
combination with the ethylene spacer. The opposite is
the case when the cyclopropyl spacer is used. The selec-
tivity versus aIIbb3 is also excellent in this series and
ranges from 40 to 650, with the exception of compound
20 which contains the vinyl-spacer. An interesting SAR
is observed in the sulfonamide side chain series (Table
2). No major differences in potency are observed in the
K/avb3 binding assay, however, when the 293-cell
attachment assay is used, the SAR becomes more evi-
dent. Clearly, aromatic side chains are preferred over
alkyl chains. IC50 values for antagonists containing
alkyl side chains are in the 100-nM range (41–46)
with the exception of the n-propyl group, which has
an IC50 value of 22 nM. Antagonists with aromatic
sulfonamide side chains (34–39) are extremely potent
with IC50 values in the low nanomolar range. How-
ever, the affinity for aIIbb3 is also increased. Com-
pound 37, which contains the biphenyl sulfonamide
side chain, shows an IC50 of 3 nM for K/avb3 binding
and 9 nM for Fg/aIIbb3 binding and is a representative
for a dual inhibitor.
Lipophilic side chain
The influence of the lipophilic side chain was investi-
gated in three different series: the carbamate side chains
(Table 1); the sulfonamide side chains (Table 2); and the
b-amino acids (Table 3). Of those series, the b-amino
acid containing avb3 antagonists are less active in the
293-cell attachment assay, despite good activity in the
standard binding assay. We have also observed this dif-
ference in other series when b-amino acids were incor-
Table 3. Thiophene-based avb3 antagonists with b-amino acid side
chains. All compounds are 1:1 racemic mixtures with the exception of
24, which is the pure S-enantiomer
R
X
K/avb3
IC50(nM)
Vn/293
IC50(nM)
Fg/aIIbb3
IC50(nM)
22
23
175
35
—
>10000
>10000
3610
avb3 antagonist 19 was chosen to evaluate the potency
of this series in bone resorption in the in vivo thyr-
oidectomized-parathyroidectomized (TPTX) rat model,
which measures the ability of a compound to inhibit the
parathyroid hormone stimulated calcemic response in
hypocalcemic TPTX rats.8 In this model, upon sub-
cutaneous administration, 19 showed a dose dependent
effect, the inhibition was ꢁ6% (0.1 mg/kgꢂ2), ꢁ26%
(0.3 mg/kgꢂ2) and ꢁ56% (1.0 mg/kgꢂ2).
24
25
26
27
28
29
30
31
32
9
10
33
32
8
1430
1730
>10000
>10000
10000
>10000
>5000
41000
>5000
15000
10500
20900
>10000
>10000
>10000
>10000
>10000
>100000
In conclusion, we have discovered a new class of potent
and selective avb3 antagonists based on a central thio-
phene scaffold and the acylguanidine Arg-mimetic. The
compounds are capable of inhibiting bone resorption in
vivo and therefore are promising drug substances for
the treatment of osteoporosis.
16
120
69
175
References and Notes
1. Hynes, R. O. Cell 1992, 69, 11.
2. Miller, W. H.; Keenan, R. M.; Willette, R. N.; Lark, M. W.
Drug Disc.Today 2000, 5, 397.
3. Hartman, G. D.; Duggan, M. E. Expert Opin.Invest.Drugs
2000, 9, 1281.
4. Peyman, A.; Wehner, V.; Knolle, J.; Stilz, H. U.; Breipohl,
G.; Scheunemann, K. H.; Carniato, D.; Ruxer, J. M.; Gourvest,