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€
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OH
F
F
O
O
F
H
N
N
N
H
O
F
COOH
IC50, lMa
27
R
Compds
R
O
21
O
22
12
Br
7. (a) Tsantrizos, Y. S.; Bolger, G.; Bonneau, P.; Cameron,
D. R.; Goudreau, N.; Kukolj, G.; LaPlante, S. R.; Llinas-
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Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bos, M.;
Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher,
Cl
O
O
23
24
na
11
ꢀ
A.-M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace,
O
L.; LaPlante, S. R.; Narjes, H.; Poupart, M.-A.; Rancourt,
J.; Sentjens, R. E.; George, R. St.; Simoneau, B.; Stein-
mann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.;
Yong, C.-L.; Llinas-Brunet, M. Nature 2003, 426, 186–
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25
32
a na means IC50 > 100 lM.
8. Nizi, E.; Koch, U.; Ponzi, S.; Matassa, V. G.; Gardelli, C.
Bioorg. Med. Chem. Lett. 2002, 12, 3325–3328.
9. Narjes, F.; Koehler, K. F.; Koch, U.; Gerlach, B.;
In summary, we have shown that also in the non-
covalent series of tripeptide phenethylamide inhibitors,
an a-hydroxy acid is a viable replacement for the P3-
aminoacid, obtaining compounds with lower peptidic
character. The preferred (S)-configuration was correctly
inferred from molecular modeling. Compounds like 14,
17, 22 and 24 are active at the low micromolar level and
no longer contain the serine trap present in 1.
€
Colarusso, S.; Steinkuhler, C.; Brunetti, M.; Altamura,
S.; De Francesco, R.; Matassa, V. G. Bioorg. Med. Chem.
Lett. 2002, 12, 701–704.
10. Narjes, F.; Brunetti, M.; Colarusso, S.; Gerlach, B.; Koch,
U.; Biasiol, G.; Fattori, D.; De Francesco, R.; Matassa,
€
V. G.; Steinkuhler, C. Biochemistry 2000, 39, 1849–1861.
11. Colarusso, S.; Koch, U.; Gerlach, B.; Steinkuhler, C.; De
€
Francesco, R.; Altamura, S.; Matassa, V. G.; Narjes, F.
J. Med. Chem. 2003, 46, 345–348.
12. Malancona, S.; Colarusso, S.; Ontoria, J. M.; Marchetti,
A.; Poma, M.; Stansfield, I.; Laufer, R.; Di Marco, A.;
Taliani, M.; Gonzalez-Paz, O.; Matassa, V. G.; Narjes, F.,
submitted for publication.
Acknowledgements
The authors gratefully acknowledge Sergio Altamura
€
13. Summa, V.; Pace Napoleone, M. P.; Petrocchi, A.
Unpublished results.
and Christian Steinkuhler for the assay data, Fabio
14. Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; Gold, E. H.;
Sommer, J. A.; Brown, A. D.; Chiu, P. J. S.; Moran, R.;
Sybertz, E. J.; Baum, T. J. Med. Chem. 1988, 31, 875–
885.
Bonelli and Francesca Naimo for the analytical data,
Silvia Pesci and Daniel Cicero for NMR spectra, Clau-
dio Giuliano for synthetic support and Michael Rowley
for valuable discussions. This work was supported in
part by a grant from the MIUR.
15. Gallinari, P.; Paolini, C.; Brennan, D.; Nardi, C.;
€
Steinkuhler, C.; De Francesco, R. Biochemistry 1999, 38,
5620–5632.
16. Di Marco, S.; Rizzi, M.; Volpari, C.; Walsh, M. A.;
Narjes, F.; Colarusso, S.; De Francesco, R.; Matassa, V.
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17. Orvieto, F.; Koch, U.; Matassa, V. G.; Muraglia, E.
Bioorg. Med. Chem. Lett. 2003, 13, 2745–2748 (compound
9 of this reference containing an unoptimized phenethyl-
amide has an IC50 of 11 lM).
References and notes
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