A. A. Krysko et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5533–5535
5535
Tjoeng, F. S.; Lindmark, R. J.; Toth, M. V.; Zupec, M. E.;
McMackins, D. E.; Adams, S. P.; Miyano, M.; Markos,
C. S.; Milton, M. N.; Paulson, S.; Herin, M.; Jacqmin, P.;
Nicholson, N. S.; Panzerknodle, S. G.; Haas, N. F.; Page,
J. D.; Szalony, J. A.; Taite, B. B.; Salyers, A. K.; King, L.
W.; Campion, J. G.; Feigen, L. P. J. Med. Chem. 1995, 38,
2378–2394.
FITC-Fg binding to its receptor in suspension of washed
human platelets with IC50 values of 0.014lM (for 9a)
and 0.0083lM (for 9b). At that, Ki values were of
0.0071lM and 0.0042lM for compounds 9a and 9b,
respectively.
The introduction of phenyl in b position of b-alanine
residue has led to 10-fold enhancement in the antiaggre-
gatory activity and affinity for aIIbb3 of the compound
9b. Similar tendency can be observed, also, for ABAS
series (10): at R=H, an IC50 value is of 1.09lM
(Collagen-induced platelet aggregation, dog platelet-rich
plasma), and at R=Ph, IC50 = 0.294lM (the similar
experimental conditions).3
4. Andronati, S. A.; Krysko, A. A.; Kabanov, V. M.;
Karaseva, T. L.; Kabanova, T. A. Acta Polonia Pharma-
ceut.—Drug Res. 2000, 57(Suppl.), 15–21.
1
5. For 4: mp 159–162°C. H NMR (300MHz, DMSO-d6) d
1.47 (s, 9H), 4.67 (s, 4H), 7.59 (dd, J = 2.5Hz, J = 8.4Hz,
1H), 8.18 (dd, J = 1.9Hz, J = 8.4Hz, 1H), 8.23 (s, 1H). MS
(FAB): 265 (M+H). For 6: mp 205–207°C. 1H NMR
(300MHz, DMFA-d7): d 1.49 (s, 9H), 2.62–2.70 (m, 4H),
4.58 (dd, J = 5.9Hz, J = 10.0Hz, 4H), 7.26 (dd J = 4.8Hz,
J = 9.1Hz, 1H), 7.53 (d, J = 9.1Hz, 1H), 7.75 (d,
J = 9.1Hz, 1H), 10.12 (s, 1H). MS (FAB): 335 (M+H).
6. For 7a: mp 145–148°C. 1H NMR (300MHz, DMFA-d7) d
1.49 (s, 9H), 2.50–2.56 (m, 4H), 2.66 (t, J = 6.8Hz, 2H),
3.41 (q, J = 6.8Hz, 2H), 3.63 (s, 3H), 4.58 (dd, J = 6.3Hz,
J = 9.8Hz, 4H), 7.26 (dd J = 4.8Hz, J = 8.7Hz, 1H), 7.53
(d, J = 8.7Hz, 1H), 7.75 (d, J = 8.7Hz, 1H), 8.00 (t,
J = 5.6Hz, 1H), 10.08 (s, 1H). MS (FAB): 420 (M+H).
For 7b: The oil. 1H NMR (300MHz, DMSO-d6) d 1.45 (s,
9H), 2.41–2.57 (m, 4H), 2.73–2.77 (m, 2H), 3.55 (s, 3H),
4.53 (t, J = 7.3Hz, 4H), 5.22 (q, J = 7.8Hz, 1H), 7.19–7.33
(m, 6H), 7.40 (dd, J = 1.4Hz, J = 8.4Hz, 1H), 7.61 (d,
J = 19.6Hz, 1H), 8.47 (d, J = 8.4Hz, 1H), 9.97 (s, 1H). MS
(FAB): 496 (M+H). For 8a: mp 142–148°C. 1H NMR
(300MHz, DMFA-d7) d 1.49 (s, 9H), 2.47–2.56 (m, 4H),
2.67 (t, J = 6.8Hz, 2H), 3.40 (q, J = 6.8Hz, 2H), 4.58 (dd,
J = 6.7Hz, J = 9.4Hz, 4H), 7.26 (m, 1H), 7.53 (d,
J = 8.1Hz, 1H), 7.75 (d, J = 8.1Hz, 1H), 7.97 (t,
J = 5.6Hz, 1H), 10.10 (s, 1H). MS (FAB): 406 (M+H),
428 (M+Na). For 8b: mp 138–141°C. 1H NMR (300MHz,
DMFA-d7) d 1.49 (s, 9H), 2.57–2.69 (m, 4H), 2.83 (m, 2H),
4.58 (t, J = 6.1Hz, 4H), 5.39 (q, J = 7.5Hz, 1H), 7.21–7.45
(m, 6H), 7.53 (d, J = 8.1Hz, 1H), 7.72 (d, J = 8.1Hz, 1H),
8.46 (d, J = 8.1Hz, 1H), 10.07 (s, 1H). MS (FAB): 482
NH
2
HN
O
H
N
OH
N
H
10
O
R
O
The values for antiaggregative activity and affinity for
aIIbb3 of RGDF mimetics synthesized by us are compa-
rable with the values obtained for well-known RGDF
mimetics containing p-benzamidine group as argrinine
side function bioisoster. Furthermore, it should be men-
tioned that further synthesis of the analogs in the series
of 4-(isoindoline-5-yl)amino-4-oxobutyric acid (2) deriv-
atives is promising for the purposes of SAR studies.
The experimental data obtained for antiaggregatory
activity and inhibition of FITC-Fg binding to fibrinogen
receptor by the novel RGDF mimetics on the base of 4-
(isoindoline-5-yl)amino-4-oxobutyric acid give the pos-
sibility to consider them as potent platelet aggregation
inhibitors and aIIbb3 antagonists.
1
(M+H), 504 (M+Na). For 9a: mp 197–200°C. H NMR
(300MHz, DMSO-d6) d 2.35–2.41 (m, 4H), 2.53–2.61 (m,
2H), 3.23 (q, J = 6.2Hz, 2H), 4.40–4.48 (m, 4H), 7.29 (d,
J = 8.2Hz, 1H), 7.48 (d, J = 8.2Hz, 1H), 7.75 (s, 1H), 8.02
(t, J = 4.7Hz, 1H), 10.06 (s, 2H), 10.22 (s, 1H). MS (FAB):
306 (M+H), 328 (M+Na). For 9b: mp 150–153°C. 1H
NMR (300MHz, DMSO-d6) d 2.42–2.56 (m, 4H), 2.6–2.69
(m, 2H), 4.40–4.47 (m, 4H), 5.39 (q, J = 7.3Hz, 1H), 7.19–
7.34 (m, 6H), 7.47 (d, J = 8.1Hz, 1H), 7.74 (s, 1H), 8.51 (d,
J = 8.1Hz, 1H), 10.05 (t, J = 5.4Hz, 2H), 10.20 (s, 1H).
MS (FAB): 382 (M+H), 404 (M+Na).
Acknowledgements
´
´
We thank Prof. J. Gonzalez-Rodrıguez (Instituto de
´
´
Quımica Fısica, CSIC, Madrid, Spain) for his help in
apply method of binding FITC-Fg and RGDF mimetics
to aIIbb3 on washed human platelets.
7. Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.;
Kelly, H. A.; Kitchin, J.; Luley, P.; Porter, B.; Ross, B. C.;
Smith, K. J.; Taylor, N. R.; Wheatcroft, J. R. J. Med.
Chem. 1994, 37, 3882.
References and notes
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